Hepatoma Res. HR Hepatoma Research 2454-2520 OAE Publishing Inc. 10.20517/2394-5079.2025.74 Review Resistance to immune checkpoint inhibitors in hepatocellular carcinoma: mechanisms and combination strategies to overcome it He Tingjiang 1 Zhang Ludan 1 Zhao Qianwei 1 2 https://orcid.org/0000-0001-6350-5573 1Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China. 2Henan Key Laboratory for Pharmacology of Liver Diseases, Zhengzhou University, Zhengzhou 450052, Henan, China. Correspondence to: Dr. Qianwei Zhao, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China. E-mail: qianwzhao@zzu.edu.cn

Received: 28 Sep 2025 | First Decision: 28 Nov 2025 | Revised: 30 Dec 2025 | Accepted: 4 Feb 2026 | Published: 14 May 2026

Academic Editor: Hongping Xia | Copy Editor: Ting-Ting Hu | Production Editor: Ting-Ting Hu

 2026 14 5 2026 12 17 © The Author(s) 2026. © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Hepatocellular carcinoma (HCC) is predominantly diagnosed at an advanced stage and ranks as the third leading cause of cancer-related mortality worldwide. In recent years, the advent and clinical application of immune checkpoint inhibitors (ICIs) have markedly transformed the therapeutic landscape of HCC, yielding superior overall survival (OS) outcomes compared with conventional targeted therapies. Nevertheless, clinical benefit is limited to a subset of patients, largely due to drug resistance. Current evidence implicates both the tumor microenvironment and tumor cell-intrinsic factors as pivotal determinants of ICI resistance. Combination strategies have emerged as a central approach in HCC therapy, significantly enhancing the antitumor activity of ICIs. Notably, ICIs plus targeted therapy (anti-angiogenic agents), dual-ICI blockade, and ICI combined with locoregional therapy (transarterial chemoembolization) currently represent the most well-established and clinically validated approaches, being approved as first- or second-line treatments. In addition, complementary approaches, including traditional Chinese medicine and modulation of intestinal microbiota, demonstrate synergistic antitumor effects when integrated with ICI, representing promising avenues for further therapeutic optimization. This review mainly elucidates the underlying mechanisms of ICI resistance and examines both established and emerging combination strategies for HCC. Furthermore, it explores potential approaches to enhance the efficacy of ICI-based regimens, with the aim of improving long-term outcomes for patients with advanced HCC.

 Hepatocellular carcinoma immune checkpoint inhibitors drug resistance combination therapy INTRODUCTION

Liver cancer remains a highly aggressive malignancy with persistently high global incidence and mortality rates, and hepatocellular carcinoma (HCC) accounts for more than 90% of all diagnosed cases[1]. Patients with HCC often face critical clinical challenges, such as late diagnosis, high rates of recurrence, and poor prognosis. With a 5-year survival rate for advanced HCC below 20%, it ranks as the third most common cause of cancer-related death globally[2]. Therefore, the development of highly effective therapeutic strategies for HCC remains a critical and urgent clinical priority.

Traditional therapeutic strategies for HCC primarily encompass surgical resection, liver transplantation, radiotherapy, chemotherapy, and targeted therapy[3]. Surgical resection is currently the preferred treatment for liver cancer, yet approximately 70% of patients experience recurrence within five years post-surgery, significantly impacting survival time[4]. Patients who underwent liver transplantation typically exhibit high survival rates and low recurrence rates. However, due to organ shortages and risk of immune rejection, only around 20% of HCC patients are eligible for liver transplantation[5]. While radiotherapy and chemotherapy can effectively inhibit tumor cell proliferation, they often damage normal tissues and generate toxic side effects due to limited target specificity[6]. Targeted therapy primarily includes multi-kinase inhibitors such as sorafenib and lenvatinib, which can effectively suppress HCC progression and reduce side effects. However, the development of drug resistance to targeted therapy makes it unsuitable for long-term use in HCC treatment[7].

Immunotherapy, represented by immune checkpoint inhibitors (ICIs), is a novel and highly effective treatment strategy for HCC. ICIs are designed to disrupt key molecular mechanisms involved in tumor immune evasion, thereby potentiating the host’s immune response against cancer. As an inflammation-driven cancer, HCC represents a promising target for immunotherapeutic interventions. ICI targeting programmed cell death protein 1 or its ligand (PD-1/PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have already been incorporated into clinical practice for advanced HCC, effectively improving patient survival. Moreover, a series of emerging immune checkpoints, including T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), lymphocyte activation gene-3 (LAG-3), T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), B7-H3 (CD276), B and T lymphocyte attenuator (BTLA), and indoleamine-2,3-dioxygenase 1 (IDO1), have been identified, and blockade of these checkpoints also demonstrates encouraging therapeutic potential in HCC patients[8-14] [Figure 1 and Table 1]. Nonetheless, emerging evidence suggests that ICI therapy is susceptible to drug resistance, posing a significant challenge to HCC immunotherapy. This review will elucidate the mechanisms underlying resistance to ICIs and explore combination strategies to overcome it, with the aim of providing new insights and therapeutic avenues to enhance ICI efficacy in HCC treatment.

Immune checkpoints and their ligands inducing immune escape of HCC cells. Created with BioRender. H, T. (2025) https://BioRender.com/ko8kl51. PD-1: Programmed cell death protein 1; PD-L1: programmed cell death ligand 1; TIM-3: T-cell immunoglobulin and mucin domain containing 3; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; LAG-3: lymphocyte-activation gene-3; TIGIT: T-cell immunoreceptor with immunoglobulin and ITIM domains; VISTA: V-domain Ig suppressor of T cell activation; BTLA: B and T lymphocyte attenuator; B7-H3: CD276.

Immune checkpoints and inhibitors used for HCC therapy

Target Drug name Approval status
PD-1 NivolumabPembrolizumabTislelizumabCamrelizumabSintilimabToripalimabNofazinlimab FDA approved (2017)FDA approved (2018)Approved in China (2024)Approved in China (2020)Approved in China (2021)In clinical trialsIn clinical trials
PD-L1 AtezolizumabDurvalumabAvelumabSugemalimabEnvafolimabAdebelimumabTQB2450 FDA approved (2017)In clinical trialsIn clinical trialsIn clinical trialsIn clinical trialsIn clinical trialsIn clinical trials
CTLA-4 IpilimumabTremelimumabIBI310 FDA approved (2020, combination therapy)FDA approved (2022, combination therapy)In clinical trials
VISTA CA-170 In clinical trials
TIGIT Tiragolumab In clinical trials
LAG-3 Relatlimab In clinical trials
BTLA Tifcemalimab In clinical trials
TIM-3 SabatolimabCobolimab In clinical trialsIn clinical trials
B7-H3 Enoblituzumab In clinical trials

PD-1: Programmed cell death protein 1; PD-L1: programmed cell death ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; VISTA: V-domain Ig suppressor of T cell activation; TIGIT: T-cell immunoreceptor with immunoglobulin and ITIM domains; LAG-3: lymphocyte-activation gene 3; BTLA: B and T lymphocyte attenuator; TIM-3: T cell immunoglobulin and mucin-domain containing-3; B7-H3: CD276.

 RESISTANCE MECHANISMS TO ICIS IN HCC

ICI therapy has achieved considerable success in the treatment of HCC. However, only 25%-40% of HCC patients benefit from this therapy, which is largely attributable to ICI resistance[15]. Based on the origin of factors contributing to ICI resistance, the underlying mechanisms primarily fall into two categories: the immunosuppressive tumor microenvironment (TME) [Figure 2] and tumor cell-intrinsic changes [Figure 3]. These mechanisms primarily involve immune system dysfunction, remodeling of the immune microenvironment, lack of neoantigens or impaired antigen presentation, dysregulated signaling pathways, metabolic reprogramming, expression of alternative immune checkpoints, and epigenetic modifications.

Immunosuppressive TME involved in ICI resistance. Created with BioRender. H, T. (2025) https://BioRender.com/1q198aq. MDSC: Myeloid-derived suppressor cells; NK: natural killer cells; Treg: regulatory T cells; DC: dendritic cells; M2: M2 macrophages; TAN: tumor-associated neutrophils; Th: helper T cells; HSC: hepatic stellate cells; LSEC: liver sinusoidal endothelial cells; CAF: cancer-associated fibroblasts; EMT: epithelial-mesenchymal transition.

Tumor cell-intrinsic factors involved in ICI resistance. Created with BioRender. H, T. (2025) https://BioRender.com/aezvlck. TF: Transcription factor; Ub: ubiquitination; Ace: acetylation; Lac: lactylation; Me: methylation; cAMP: cyclic adenosine monophosphate; ROS: reactive oxygen species; TMB: tumor mutational burden; MHC: major histocompatibility complex; IDO1: indoleamine-2,3-dioxygenase 1; PD-L1: programmed cell death ligand 1; B7-H3: CD276; lncRNA: long non-coding RNA.

 IMMUNOSUPPRESSIVE TME Dysfunction of antitumor immune cells

Among immune cells, cytotoxic CD8+ T cells, dendritic cells (DCs), and natural killer (NK) cells typically exert antitumor effects, and their dysfunction significantly impairs the efficacy of immunotherapy[16]. Liver functions as a central immunomodulatory organ that generally maintains an immune-tolerant state to ensure local and systemic protection. Studies have shown that some liver cancers are “cold tumors”, characterized by limited T-cell infiltration, a feature that contributes significantly to primary ICI resistance[17]. Defects in antigen-presenting cells (APCs), impaired T-cell activation, and T-cell exclusion further led to T-cell deficiency in HCC tissues[18]. Moreover, the absence of CD8+ T cells in liver cancer is often accompanied by an increased frequency of exhausted CD8+ T cells. These exhausted cells typically overexpress immune checkpoints such as PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT, resulting in immune tolerance. DCs contribute to antitumor immunity by presenting antigens to T cells. However, immature DCs may promote tumor tolerance through the induction of regulatory T cells (Tregs) and suppression of effector T cells[19]. Even mature DCs sometimes facilitate immune evasion by promoting Treg differentiation and secreting immunosuppressive cytokines[20]. Additionally, abnormal proportions or functional impairments in NK cells also drive ICI resistance. For example, HCC patients exhibit an increased population of Siglec-9+ NK cells with reduced cytotoxicity and disrupted homeostasis[21]. The expression of immune checkpoints such as TIGIT and TIM-3 on NK cells, along with diminished production of cytokines such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α, further attenuates the effectiveness of ICI therapy[22].

 Infiltration of immunosuppressive cells

Immunosuppressive cells within the TME represent a major mechanism underlying resistance to ICIs. These cells primarily include Kupffer cells, tumor-associated macrophages (TAMs), Tregs, and myeloid-derived suppressor cells (MDSCs). Tregs act as key negative regulators of CD8+ T cells, suppressing immune responses through expression of immune-inhibitory molecules such as CTLA-4, CD39, and CD73, as well as the secretion of immunosuppressive cytokines including interleukin (IL)-10 and transforming growth factor (TGF)-β[23]. Recent studies also indicate that Tregs can induce immunosuppression via interactions with type 2 conventional DCs[24]. Other immunosuppressive cells, including Kupffer cells, TAMs, and MDSCs, promote immune tolerance through multiple mechanisms: they facilitate the proliferation, infiltration, and activation of Tregs; upregulate checkpoint ligands (e.g., PD-L1) and immunosuppressive factors such as vascular endothelial growth factor (VEGF), arginase-1 (ARG-1), and IDO1[25,26]; inhibit the activation of CD8+ T cells and NK cells; and reduce the expression of major histocompatibility complex class II (MHC-II) and co-stimulatory molecules. Additionally, TAMs have been shown to confer ICI resistance by promoting epithelial-mesenchymal transition (EMT) of HCC cells or by forming macrophage-coated tumor clusters (MCTCs) that impede the infiltration of cytotoxic T cells[27,28]. Furthermore, emerging evidence suggests that other immune cells, including B cells, monocytes, helper T cells (Th), and tumor-associated neutrophils (TANs) also contribute to ICI resistance[29]. These cells dampen antitumor immunity by expressing immune checkpoints such as PD-1, TIM-3, CTLA-4, and chemokine receptor 4/6 (CCR4/CCR6), or accelerating the exhaustion of CD8+ T cells.

 Non-immune cells and factors involved in TME

Besides immune cells, functional alterations in other components of TME such as hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs) also contribute to ICI resistance. Studies have shown that HSCs promote the infiltration of Tregs and MDSCs into HCC tissues through the secretion of hepatocyte growth factor (HGF). Meanwhile, LSECs can suppress immune responses by expressing PD-L1 and facilitating Treg recruitment[30]. Cancer-associated fibroblasts (CAFs) represent another critical element within the TME, which secrete various cytokines, exosomes, and other effector molecules that enable tumor cells to evade immune surveillance[31]. For instance, CAFs recruit immunosuppressive cells and inhibit T cell responses through the production of TGF-β, IL-6, and chemokine ligand (CCL)2[32,33]. Furthermore, CAFs interact with TAMs to promote M2 polarization, which supports HCC proliferation and fosters an immunosuppressive environment[34]. Additionally, other TME features such as extracellular matrix remodeling, angiogenesis, the presence of immunosuppressive soluble factors, hypoxia, and the acidic conditions within tumor tissues collectively contribute to the development of ICI resistance[35,36].

 TUMOR CELL-INTRINSIC FACTORS Defects in antigen presentation

MHC ligands on tumor cells are directly recognized by T-cell receptors (TCRs) on CD8+ or CD4+ T cells and play a crucial role in antitumor immune responses. Reduced expression or impaired binding affinity of MHC ligands disrupts antigen presentation, representing a key mechanism of resistance to ICIs[37]. Studies have reported that downregulation of MHC ligands leads to diminished antitumor T cell activity[38]. Furthermore, HCC patients with low expression of MHC ligands often remain unresponsive to ICIs. Additionally, tumor mutational burden (TMB), defined as the total number of somatic mutations per megabase within the coding regions of the tumor genome, serves as a quantitative biomarker for neoantigen load and mutation frequency[39]. Theoretically, a higher TMB increases the diversity and immunogenicity of neoantigens, thereby enhancing T-cell-mediated tumor killing[40]. As a result, elevated TMB is associated with improved response to ICIs, whereas tumors with low TMB frequently exhibit reduced immunogenicity, which constitutes a major mechanism of primary resistance to ICIs in HCC patients[40].

 Abnormal immune checkpoint expression

Tumor cells often exploit immune checkpoints (e.g., PD-L1, CTLA-4) to evade cytotoxic T-cell-mediated antitumor immunity[41]. However, the absence or low expression of immune checkpoints leads to a lack of response to ICI therapy, a phenomenon known as primary resistance. Additionally, compensatory upregulation of alternative immune checkpoints also undermines the efficacy of ICIs, typically contributing to acquired resistance. For example, treatment of HCC patients with PD-1/PD-L1 inhibitors has been shown to upregulate the major ligand of LAG-3, resulting in immune resistance[13]. Other immune checkpoints such as TIM-3, TIGIT, and BTLA have been reported to promote T-cell exhaustion under conditions of chronic antigen stimulation or down-regulation of IFN-γ, further enhancing resistance to PD-1/PD-L1 inhibitors in HCC[10,12,14]. Moreover, increased expression of IDO1 in HCC prevents phagocytosis of macrophages, and its inhibition enhances the efficacy of anti-PD-1 therapy[8]. Recently, two emerging immune checkpoints, including B7-H3 and VISTA (PD-1 homolog), have also been shown to promote immune escape by inhibiting the infiltration and activation of T cells in HCC[11,42].

 Dysregulation of immune-associated signaling pathways

The TGF-β-induced pathway represents one of the most extensively studied mechanisms underlying resistance to ICIs in HCC. First, TGF-β1 upregulates the expression of PD-L1 and B7-H3 during EMT in HCC cells[43]. Additionally, TGF-β secreted by HCC cells not only exerts inhibitory effects on NK cells and DCs, but also suppresses CD8+ T cell activity and promotes its exhaustion by downregulating IFN-γ and upregulating PD-1[44,45]. Furthermore, TGF-β enhances the immunosuppressive microenvironment within HCC tissues by promoting eosinophil and mast cell chemotaxis, inducing M2-type macrophage polarization, and amplifying Tregs activity[46,47]. Abnormal activation of the WNT/β-catenin pathway is another key contributor to ICI resistance in HCC. Approximately 30% of HCC patients harbor catenin beta-1 gene (CTNNB1) mutations (encoding β-catenin), which are associated with non-response to ICIs[48]. β-Catenin activation also reduces the expression of chemokines such as CCL1 and CCL4, impairs the infiltration of DCs and antigen-specific T cells, and suppresses NK cell activity, thereby diminishing the antitumor efficacy of ICIs[49,50]. Moreover, activation of the mitogen-activated protein kinase (MAPK) signaling pathway influences both immune-cell infiltration and immune checkpoint expression. For example, the epidermal growth factor receptor (EGFR)-p38 MAPK and MAPK/nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) axes enhance PD-L1 and CD274 expression to facilitate immune escape[51-53]. Other signaling pathways including IFN-γ/janus kinase/signal transducer and activator of transcription (JAK/STAT), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), and NF-κB have also been implicated in ICI resistance through the regulation of cytokines and immune checkpoints (e.g., TGF-β, VEGF, type I interferon, PD-L1) expression, modulation of immune-cell function [e.g., NK cells, T helper 1 (Th1) cells, CD8+ T cells], and promotion of Treg accumulation[54-56].

 Epigenetic modifications

Epigenetic modifications influence the efficacy of ICIs primarily by regulating the expression of effector genes, and the mechanisms include DNA and histone modifications, non-coding RNAs, and chromatin remodeling. Studies have shown that DNA methyltransferases (DNMTs)-induced hypermethylation suppresses MHC class I (MHC-I) expression, leading to impaired tumor antigen presentation[57]. Additionally, histone methyltransferases [e.g., enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), SET domain bifurcated histone Llysine methyltransferase 1 (SETDB1), protein arginine methyltransferase 5 (PRMT5), and methyltransferase like 1/3 (METTL1/3)] and demethylases [e.g., lysine demethylase 1 (KDM1)] modulate the expression of PD-L1, MHC-II, and chemokines [e.g., C-X-C motif chemokine ligand 5 (CXCL5), CXCL8, CXCL10] in HCC cells. These changes inhibit the infiltration and function of NK cells and CD8+ T cells while enhancing the recruitment of MDSCs[58,59]. Furthermore, histone acetylation and deacetylation modifications mediated by enzymes such as lysine acetyltransferase 2A (KAT2A) and histone deacetylase (HDAC) 8 alter the function and abundance of Tregs and CD8+ T cells within the TME through chemokine regulation, and ultimately compromise ICI efficacy in HCC. Emerging evidence indicates that post-translational modifications (PTMs) on non-histone proteins also play important roles in modulating ICI response[60]. For instance, deacetylase silent information regulator 2 (SIRT2) and HDAC2 have been reported to promote immune escape by regulating the stability of fibrinogen-like protein 1 (FGL1) and the subcellular localization of PD-L1[61,62]. Moreover, high expression of HDAC1, HDAC2, and HDAC3 in HCC patients is associated with suppressed IFN-γ pathway activity, enhanced T-cell exclusion, and increased MDSC accumulation, contributing to ICI non-responsiveness[63]. Non-coding RNAs, including microRNAs and long non-coding RNAs (lncRNAs), represent another important class of epigenetic regulators affecting ICI efficacy in HCC. For example, miR-455 and lncRNA myocardial infarction associated transcript (MIAT) have been shown to dampen antitumor immune responses by modulating PD-L1 expression[64,65].

 Tumor cell-derived metabolites and exosomes

Metabolites secreted by tumor cells influence the immune status of HCC primarily by modulating the function and infiltration of immune cells within the TME. Multiple studies indicate that enhanced aerobic glycolysis in tumor cells leads to substantial lactate release, acidifying the TME and promoting the infiltration of immunosuppressive cells. Lactate also drives M2 macrophage polarization while inhibiting the activities of CD8+ T cells, NK cells, and DCs[66]. Furthermore, dysregulated lipid metabolism in HCC reduces the abundance of CD4+ T cells and M1 macrophages and impairs NK cell function[67,68]. For instance, in obesity-associated HCC models, tumor-derived prostaglandin E2 (PGE2) binds to the prostaglandin E2 receptor 4 (EP4) receptor on immune cells, suppressing the expression of IFN-γ and TNF-α while inducing IL-10 and IL-6[69]. Additionally, HCC-secreted oleic acid (OA) promotes an immunosuppressive phenotype in macrophages, and its inhibition enhances the antitumor effects of anti-PD-1 therapy[70]. Clinical evidence suggests that elevated asparagine or glutamine metabolism in HCC patients is associated with increased infiltration of Tregs, macrophages, and memory B cells, fostering an immunosuppressive TME[71,72]. Inhibition of glutamine metabolism significantly improves response to ICIs in HCC[72]. Moreover, the accumulation of cyclic adenosine monophosphate (cAMP) has been shown to suppress CD4+ and CD8+ T cell responses while enhancing Treg activity through binding to adenosine A2A receptor (A2AR)[73]. In addition, exosomes carrying microRNAs, circular RNAs, lncRNAs, and proteins such as PD-1/PD-L1 collectively attenuate the cytotoxicity of T cells and NK cells[74]. Moreover, exosomes from tumor cells promote the infiltration of M2 macrophages, Tregs, DCs, and N2 neutrophils, as well as angiogenesis, further driving resistance to ICI therapy[75-77].

 COMBINATION THERAPY FOR OVERCOMING DRUG RESISTANCE TO ICIS

Combination therapy has emerged as a key strategy to overcome resistance and improve outcomes with ICIs. Evidence demonstrates that multimodal therapeutic approaches enhance ICI efficacy through mechanisms such as counteracting immunosuppressive elements, promoting antigen release and presentation, activating and expanding effector T cells, and improving CD8+ T-cell infiltration and function [Table 2][39,78-99]. Recently, combination therapy has become a foundational approach in HCC, primarily including strategies such as ICI plus targeted therapy, dual-ICI, ICI combined with locoregional therapy, ICI integrated with traditional Chinese medicine (TCM), and ICI combined with intestinal microbiota modulation.

Combination strategies and their underlying mechanisms in promoting ICI efficacy used in clinical trials for HCC treatment

ICI Target Combination (target) Sensitization mechanism Outcome Trial numbers (current status)
Nivolumab PD-1 Ipilimumab (CTLA-4) Boost the activation and proliferation of T cells ORR: 24%, mOS: 16.4 months NCT03222076[80] (Second-line treatment)
Relatlimab (LAG-3) + Bevacizumab (VEGF) Inhibit LAG-3 checkpoint, enhance T-cell function; suppress angiogenesis, promote T-cell infiltration and efficacy Underway NCT05337137[81]
Lenvatinib (TKI) Inhibit tumor angiogenesis and cancer cell proliferation, promote immune activity ORR: 54.2%, PFS: 73.9 months NCT04039607[82]
Cabozantinib (TKI) Inhibit VEGF-driven angiogenesis and reduce immunosuppressive cells, promote immune cell infiltration ORR: 19%, 1-year OSR: 12%-38.3% NCT03299946[83]
Pembrolizumab PD-1 Lenvatinib (TKI) Block tumor angiogenesis (blood vessel formation) and suppress tumor cell proliferation mPFS: 9.3 months, mOS: 22 months NCT03713593[84] (First-line treatment)
Lenvatinib (TKI) + TACE Inhibit tumor angiogenesis and proliferation; induce localized tumor necrosis and release tumor antigens mPFS: 14.6 months, 24-month OSR: 75% NCT04246177[85] (First-line treatment)
Regorafenib (TKI) Suppress tumor growth by blocking oncogenic signaling pathways and modulating the immunosuppressive TME ORR: 29%, PFS: 6.8 months NCT03347292[86]
Camrelizumab PD-1 Apatinib (VEGFR inhibitor) Normalize tumor vasculature and suppress immunosuppressive cells mPFS: 5.6 months, mOS: 22.1 months NCT04297202[87] (First-line treatment)
Apatinib (VEGFR inhibitor) + TACE Induce localized tumor ischemia and necrosis, release tumor antigens and promote inflammatory microenvironment; inhibit angiogenesis, improve immune cell infiltration mPFS: 13.5 months, mOS: 22.1 months NCT04559607[88]
Sintilimab PD-1 IBI305 (VEGF inhibitor) Suppress blood vessel growth, modulate the immune-suppressive TME mPFS: 4.6 months NCT03794440[89]
IBI310 (CTLA-4 inhibitor) Promote T-cell activation and proliferation mPFS: 3.9 months, 6-month OSR: 93.1% NCT04401813[90]
Bevacizumab (VEGF inhibitor) Inhibit VEGF-driven angiogenesis, improve T-cell infiltration ORR: 21%, PFS: 4.6 months NCT04843943[91] (First-line treatment)
Penpulimab PD-1 Anlotinib (TKI) Suppress tumor angiogenesis and proliferation ORR: 24%, PFS: 5.4 months NCT04344158[92]
Durvalumab PD-L1 Tremelimumab (CTLA-4 inhibitor) Inhibit CTLA-4, promote T-cell activation and proliferation ORR: 33%, PFS: 19.53 months NCT03298451[93] (First-line treatment)
Bevacizumab (VEGF inhibitor) Inhibit VEGF-driven angiogenesis and modulating the immunosuppressive TME mPFS: 14.2 months NCT02519348[94]
Bevacizumab (VEGF inhibitor) + TACE Normalize tumor vasculature; induce localized tumor cell death, release neoantigens and promote immune cell infiltration Underway NCT03778957[95]
Atezolizumab PD-L1 Bevacizumab (VEGF inhibitor) Inhibit VEGF to normalize tumor vasculature, reduce immunosuppression and promote T-cell infiltration 12-month OSR: 67.2%, mPFS: 6.8 months NCT03434379[96] (First-line treatment)
Bevacizumab (VEGF inhibitor) + TACE Inhibit angiogenesis, reduce Treg activity and enhance DC maturation; induce localized tumor necrosis, release tumor antigens and promote immune cell infiltration 13-month OSR: 75.4%, mPFS: 7.03 months NCT05776875[97]
Cabozantinib (TKI) Suppress tumor angiogenesis, proliferation and metastasis Underway NCT03755791[98]
Sorafenib (TKI) Inhibit tumor proliferation and angiogenesis 12-month OSR: 54.6%, mPFS: 4.3 months NCT03434379[96]
Cobolimab TIM-3 Dostarlimab (PD-1) Enhance T-cell reactivation and proliferation Underway NCT03680508[99]

PD-1: Programmed cell death protein 1; PD-L1: programmed cell death ligand 1; TIM-3: T-cell immunoglobulin and mucin domain containing 3; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; LAG-3: lymphocyte activation gene 3; VEGF: vascular endothelial growth factor; TKI: tyrosine kinase inhibitor; TACE: transarterial chemoembolization; VEGFR: vascular endothelial growth factor receptor; TME: tumor microenvironment; DCs: dendritic cells; ORR: objective response rate; PFS: progression-free survival; mPFS: median progression-free survival; OSR: overall survival rate; mOS: median overall survival.

 ICIS COMBINED WITH TARGETED THERAPY Tyrosine kinase inhibitors

The combination of ICIs with anti-angiogenic agents represents one of the most extensively studied treatment regimens and has opened new avenues for the management of advanced HCC. Among anti-angiogenic drugs, tyrosine kinase inhibitors (TKIs) such as sorafenib, lenvatinib, regorafenib, and cabozantinib have been shown to enhance the response to PD-1 inhibitors by promoting CD8+ T-cell infiltration, suppressing M2 macrophage polarization, and reducing the infiltration of Th cells and Tregs[100-102]. Additionally, TKIs downregulate immunosuppressive cytokines including IL-10 and TGF-β, as well as immune checkpoints such as PD-1 and TIM-3, thereby helping to restore sensitivity to PD-1 blockade[103-105]. These mechanistic insights support the combined use of TKIs and ICIs as a novel therapeutic strategy in HCC. Recently, a growing number of clinical trials evaluating ICI-TKI combinations have been conducted in HCC patients, with several demonstrating superior antitumor activity compared to monotherapy. For example, the combination of cabozantinib with atezolizumab prolongs progression-free survival (PFS) of HCC patients, although no significant overall survival (OS) benefit is observed[98]. In addition, PD-1 inhibitors combined with TKIs such as regorafenib and lenvatinib yield higher objective response rates (ORR), longer PFS, and improved OS in patients with unresectable HCC[106]. Notably, the combination of pembrolizumab and lenvatinib has demonstrated significant efficacy, establishing it as a first-line treatment for advanced HCC[84].

 VEGF or VEGFR inhibitors

Studies have shown that inhibitors targeting VEGF or vascular endothelial growth factor receptor (VEGFR) reduce the infiltration and activity of immunosuppressive cells. In addition, anti-VEGF/VEGFR therapy inhibits M2-type macrophage polarization and downregulates the expression of immune checkpoint (e.g., PD-L1/PD-L2) and immunosuppressive factors (e.g., IL-6, IDO1, and IL-10), while promoting DC maturation and antigen presentation[107,108]. These findings indicate that VEGF/VEGFR inhibitors can alleviate immunosuppression in the TME and possibly help to overcome resistance to ICIs. Consistently, clinical trials demonstrate that combining ICIs with anti-VEGF or anti-VEGFR agents leads to improved efficacy in HCC treatment. In particular, the combination of PD-L1 inhibitor atezolizumab with VEGF inhibitor bevacizumab has been approved as a first-line treatment for HCC[109]. Another clinical trial reveals that the VEGFR inhibitor rivoceranib (apatinib) combined with PD-1 inhibitor camrelizumab significantly improves both PFS and OS in patients with unresectable HCC[110]. Furthermore, a series of ongoing clinical trials are evaluating the efficacy of ICI-based combinations with other VEGFR inhibitors, such as anlotinib and cabozantinib, which may offer new combination strategies, particularly for patients with advanced HCC[41].

 Other targeted drugs

In addition to anti-angiogenic agents, the combination of ICIs with other targeted drugs has also demonstrated improved efficacy in patients with HCC. For instance, the TGF-β receptor I inhibitor galunisertib significantly enhances the antitumor activity of PD-L1 inhibitors by suppressing TGF-β signaling[111]. Similarly, a peroxisome proliferator-activated receptor (PPAR) γ antagonist resensitizes tumors to anti-PD-L1 therapy in HCC models by inhibiting PPARγ/vascular endothelial growth factor A (VEGF-A)-mediated immunosuppression[112]. Furthermore, DNA damage repair (DDR) inhibitors are demonstrated to enhance the clinical efficacy of ICIs in HCC through mechanisms such as promoting neoantigen release, increasing TMB, and upregulating PD-L1 expression[113]. Currently, more than 80 clinical trials are investigating the therapeutic potential of combining DDR-targeted agents with ICIs, with several studies reporting favorable tolerability and significant antitumor activity[114,115]. Additionally, the combination of PD-1 blockade with the phosphatidylserine-targeting agent bavituximab has been shown to prolong the PFS and OS of HCC patients[116]. Preclinical studies also indicate that PEGylated IFN-α enhances the efficacy of PD-1 inhibitors by promoting the infiltration and activation of CD8+ T cells[117]. Epigenetic inhibitors targeting HDACs or DNMTs are reported to improve ICI response by modulating the infiltration of CD8+ T cells and IL-17-producing Th cells, as well as PD-1/PD-L1 expression, providing a rationale for combining epigenetic therapies with ICIs[118,119]. Recently, inhibitors of carbonic anhydrase XII, a novel class of anticancer agents, have shown the ability to remodel the immunosuppressive TME, suggesting another promising combination strategy for HCC treatment[120].

In conclusion, therapeutic approaches that combine targeted agents with ICIs to overcome ICI resistance are strongly supported by robust clinical trial evidence. In particular, the combination of ICIs with anti-angiogenic agents has gained approval in multiple countries as first‑line and second‑line treatments for HCC, demonstrating considerable promise for clinical application.

 DUAL-ICIS COMBINATION THERAPY

The combination of PD-1/PD-L1 inhibitors and CTLA-4 inhibitors represents one of the most frequently evaluated strategies in clinical trials, as it enhances antitumor immunity through complementary mechanisms of T-cell activation. For example, the combination of nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor) significantly improves ORR and OS in patients with HCC[121]. This regimen received Food and Drug Administration (FDA) approval as a second-line treatment for advanced HCC previously treated with sorafenib. Similarly, clinical trials evaluating durvalumab (PD-L1 inhibitor) in combination with tremelimumab (CTLA-4 inhibitor) demonstrate promising therapeutic outcomes[122], and this combination was approved in 2022 for the first-line treatment of unresectable HCC. Recent findings from a phase III trial indicate that tremelimumab plus durvalumab significantly extends OS of HCC patients compared to monotherapy[123]. Additionally, the combination of sintilimab (PD-1 inhibitor) and IBI310 (CTLA-4 inhibitor) has shown encouraging efficacy in clinical trials. Based on these findings, this combination was approved in 2021 as a first-line treatment for unresectable or metastatic HCC[90].

In addition to CTLA-4 inhibitors, combinations of PD-1/PD-L1 inhibitors and other ICIs are also under investigation. For instance, clinical evidence suggests that PD-L1 inhibitors sometimes induce complete tumor eradication in HCC patients who have developed acquired resistance to PD-1 inhibitors[124]. The combination of the TIM-3 inhibitor cobolimab with dostarlimab has demonstrated acceptable safety and encouraging clinical activity as a first-line treatment for advanced HCC[125]. Furthermore, the LAG-3 inhibitor relatlimab and IDO1 inhibitor abrine significantly enhance antitumor efficacy when combined with anti-PD-1 therapy[8]. Recently, several clinical trials evaluating inhibitors targeting TIM-3, LAG-3, or TIGIT in combination with other ICIs for HCC treatment are currently underway[126,127]. Positive results from preclinical HCC models may offer promising new dual-ICI therapeutic options for HCC.

As one of the well-established combination strategies, dual-ICI therapy is backed by substantial clinical trial evidence, laying a solid foundation for the clinical application of PD-1/PD-L1 inhibitors combination with CTLA-4 inhibitors in HCC treatment. In the future, with the discovery of novel ICIs and corresponding inhibitors, an increasing number of ICI-based combinations are expected to enter clinical practice for HCC management.

 ICIS COMBINED WITH LOCOREGIONAL THERAPY

Locoregional therapies constitute a group of liver-directed interventions that augment the immunogenicity of residual tumor cells and potentiate their susceptibility to immunotherapy. Accumulating evidence indicates that locoregional modalities enhance responsiveness to ICIs through mechanisms including the upregulation of tumor-associated antigens (TAAs) and enhanced immunogenicity, promotion of DC and CD8+ T-cell infiltration, and release of pro-inflammatory cytokines (e.g., TNF-α, IL-12)[128]. In addition, locoregional therapies mitigate the activities of immunosuppressive cells and elicit immunogenic cell death (ICD)[129]. Together, these mechanisms underpin the rational combination of locoregional therapy with ICIs as a promising strategy to amplify antitumor immunity[130].

In recent years, multiple studies have evaluated the efficacy and safety of combining ICIs with transarterial chemoembolization (TACE) for the treatment of HCC. A phase III trial demonstrates that combining lenvatinib, pembrolizumab, and TACE significantly prolongs PFS of patients with unresectable HCC, with some achieving complete tumor regression[131]. Another study shows that adding anti-PD-L1 and targeted drugs to TACE improves both OS and ORR of HCC patients[132]. A clinical trial conducted by Roche showed that atezolizumab plus bevacizumab combined with TACE led to significant benefits in unresectable HCC, highlighting the synergy between ICIs, anti-angiogenic therapy, and locoregional treatment[97]. Studies on hepatic arterial infusion chemotherapy (HAIC) combined with ICIs have also shown promise in improving the antitumor efficacy. A retrospective analysis finds that HAIC combined with ICIs and TKIs offers a favorable safety profile and better liver function preservation in intermediate and advanced HCC[133]. Furthermore, an ongoing trial is investigating concurrent hepatic arterial delivery of a PD-L1 antibody with FOLFOX chemotherapy to enhance local immune blockade and suppress tumor immune evasion[134]. Radiotherapy eliminates tumor cells within the irradiated field through high-energy radiation and elicits systemic immune effects, making it a promising partner for immunotherapy[135]. Supported by positive outcomes from phase I/II trials, the combination of radiotherapy [e.g., Yttrium-90 (Y90)] with ICIs is being increasingly explored in advanced HCC[136]. Similarly, thermal ablation techniques including microwave ablation (MWA) and radiofrequency ablation (RFA) can also mitigate local immunosuppression and synergize effectively with ICIs[130].

In summary, locoregional therapies represented by TACE combined with ICIs have accumulated abundant clinical trial evidence in the management of HCC. Approved for clinical application in HCC treatment, this combination regimen has emerged as an effective therapeutic strategy to overcome ICI resistance.

 ICIS COMBINED WITH TCM

The combination of PD-1/PD-L1 inhibitors with TCM has shown superior efficacy compared to ICI monotherapy in the treatment of HCC. For instance, ginseng-derived nanoparticles (GDNPs) and Huaier enhance the antitumor effect of PD-1/PD-L1 inhibitors by promoting M1 macrophage polarization and recruiting CD8+ T cells into the TME[137,138]. Similarly, natural compounds such as bufalin and curcumin (isolated from turmeric) potentiate the activity of anti-PD-L1 antibodies by shifting TAMs from M2 to M1 phenotype and downregulating PD-1 expression on CD8+ T cells[139,140]. Other TCM-derived agents, including icaritin, luteolin, baicalein and baicalin, and osthole have been shown to induce antitumor immune responses through regulating immune cell function[141-143]. Additionally, YIV-906, a standardized formulation derived from Huang Qin Tang, reduces M2 polarization and enhances antitumor activity when combined with PD-1 inhibition[144]. Besides, a clinical trial is currently underway to evaluate the efficacy of Huaier granules in combination with atezolizumab (anti-PD-L1) and bevacizumab in patients with HCC[145].

Furthermore, the emergence of new immune checkpoints opens new avenues for combining TCM with ICIs in the treatment of HCC. For example, network pharmacological analyses suggest that the herbal medicine Yinchen may activate immune cells by suppressing CTLA-4 and LAG-3[146]. Abrine, a compound derived from Abrus cantoniensis, is identified as a specific inhibitor of IDO1. Studies also demonstrate that abrine synergizes with PD-1 inhibitors to suppress HCC progression by downregulating IDO1 and PD-L1 expression while enhancing CD8+ T-cell infiltration within tumors[8]. Moreover, the YANGYIN Fuzheng Jiedu prescription has been shown to inhibit tumor growth in HCC models by alleviating exhausted T cells and reducing the expression of immune checkpoints, including PD-1, TIM-3, and TIGIT[147,148]. These mechanisms highlight the potential of TCM agents as promising candidates for combination strategies with ICIs in HCC therapy.

Although TCM has exhibited considerable application potential in enhancing the efficacy of ICI therapy, most relevant studies are still in the preclinical exploration stage. In the future, more mechanistic research and clinical trials are needed to clarify its prospects for clinical application in HCC treatment.

 ICIS COMBINED WITH INTESTINAL MICROBIOTA

Increasing evidence indicates a strong correlation between the composition of the gut microbiome and clinical outcomes following ICI treatment in patients with HCC. For instance, a higher abundance of Lachnospiraceae bacterium-GAM79, Alistipes sp. Marseille-P5997, Bifidobacterium, Coprococcus, Akkermansia, and Acidaminococcus is associated with improved responses to ICIs in HCC[149-152]. Studies indicate that specific intestinal bacteria, including Bifidobacterium and Bacteroides fragilis, restore response to ICIs by promoting the activation of DCs, CD8+ T cells, and Th1 cells[153,154]. Additionally, Akkermansia muciniphila, whose abundance decreases during metabolic dysfunction-associated fatty liver disease (MAFLD)-promoted hepatocarcinogenesis, has been shown to exert maximal tumor-suppressive effects in HCC models when combined with PD-1 inhibition[149]. Moreover, metabolites such as ursodeoxycholic acid and ursocholic acid, which correlate with the abundance of Lachnoclostridium, are significantly enriched in fecal samples from HCC patients who respond to ICI therapy[155]. These findings underscore the potential of combining ICIs with microbiota-targeted interventions to enhance the efficacy of immunotherapy in HCC.

Probiotic supplementation, fecal microbiota transplantation (FMT), and antibiotic modulation have emerged as promising strategies to enhance the efficacy of ICIs in HCC. For instance, probiotic strains such as Lactobacillus rhamnosus Probio-M9, Lachnospiraceae bacterium-GAM79, Ruminococcus, and Bifidobacterium bifidum are associated with improved ICI efficacy[153,156,157]. Moreover, several studies showed that FMT enhances antitumor efficacy of ICIs, and combining FMT with atezolizumab or bevacizumab prolonged both PFS and OS of HCC patients[158,159]. The use of antibiotics in combination with ICIs represents another emerging approach, and vancomycin has been shown to improve the efficacy of nivolumab in patients with refractory primary or metastatic HCC[160]. However, the impact of antibiotics on ICI therapy remains controversial and warrants further investigation.

In summary, combining ICIs with gut microbiota modulation has demonstrated promising efficacy in overcoming ICI resistance in HCC. Nevertheless, its clinical translation is hampered by insufficient understanding of the underlying mechanisms and a lack of robust clinical evidence. Further well‑designed trials are essential to advance this therapeutic strategy toward clinical application.

 CONCLUSION AND FUTURE PERSPECTIVES

ICIs have ushered in a paradigm shift in the treatment of HCC, offering the potential for durable antitumor responses. However, the emergence of drug resistance remains a formidable challenge, undermining clinical outcomes and restricting the broader application of ICIs in HCC. In recent years, combination therapies have emerged as the most promising and widely adopted approaches to counteract ICI resistance. ICIs plus targeted therapy and dual-ICI blockade currently represent the most well-established and clinically validated approaches, with robust evidence from clinical trials supporting their approval as first- or second-line treatments. Moreover, the combination of ICIs with locoregional therapies has gained relatively broad application in HCC management. Notably, the combination of TACE with ICIs has demonstrated significant efficacy in delaying HCC progression in clinical trials, and the regimen of TACE plus lenvatinib and pembrolizumab was approved in China in 2025 for the treatment of unresectable non-metastatic HCC. In contrast, combinations of ICIs with TCM or microbiota modulators currently rely mainly on exploratory evidence and have not yet been substantiated for routine clinical use.

However, these combination strategies still face distinct challenges in clinical practice. For ICI-based targeted therapy combinations, key issues include the need for high-quality clinical data to support diverse regimens, lengthy trial and approval cycles, increased risks of combined drug toxicity, and the imperative for precise patient stratification. Safety profiles for dual-ICI blockade regimens are still being accumulated, and the absence of unified guidelines for managing immune-related adverse events (irAEs) complicates monitoring. Furthermore, the lack of reliable predictive biomarkers hinders the accurate identification of patients most likely to benefit. The diversity of locoregional treatment modalities further complicates the standardization of combination regimens with ICIs and the accurate assessment of therapeutic outcomes. For example, there is no consensus on the sequence, interval, or dose adjustment between locoregional and systemic therapies, which affects the consistency of treatment efficacy. The complex composition of TCM preparations poses significant challenges for quality control, making it difficult to establish unified clinical trial protocols and evaluation systems. As for microbiota-based combination therapies, major limitations currently include the lack of HCC-specific guidelines for probiotic strain selection, dosage, and treatment duration, as well as the absence of a dedicated regulatory pathway for FMT combined with ICIs.

Moreover, incompletely elucidated mechanisms of ICI resistance are another important reason for the limited therapeutic efficacy and clinical application of combination strategies. For example, while ICIs and targeted drugs have well-defined targets such as PD-1/PD-L1 and VEGF, the mechanisms underlying the production of these drug resistance-related factors remain incompletely understood. Consequently, combination therapy cannot completely overcome ICI resistance. According to the two categories of factors inducing ICI resistance displayed in this review, tumor cell intrinsic factors appear to play a dominant role. In addition to altering their own functions, tumor cells can secrete factors including cytokines and metabolites that influence TME, thereby coordinating multiple processes to evade immune surveillance. Therefore, elucidating the molecular mechanisms in tumor cells that drive ICI resistance is critical to the optimization of HCC immunotherapy. Besides, considering the importance of heterogeneity in influencing the functions of tumor cells, systematic evaluation of intra- and inter-patient heterogeneity may clarify the specific causes of ICI resistance. Moreover, intestinal microbiota has emerged as a key regulator of antitumor immunity[161]. Whether tumor cells escape immunotherapy through the intestinal microbiota requires further investigation, which will expand our understanding of ICI resistance mechanisms.

Given the complex and variable mechanisms that induce ICI resistance, staged combination therapy represents a promising direction for HCC. Beyond currently established regimens, innovative approaches such as cellular immunotherapies [e.g., chimeric antigen receptor T (CAR-T) cells, chimeric antigen receptor (CAR)-NK, and CAR-macrophage (CAR-M)][162-164], inhibitors targeting immunosuppressive metabolites (e.g., adenosine and lactate)[165,166], and oncolytic viruses [e.g., talimogene laherparepvec and pexastimogene devacirepvec (JX-594)] show promise in augmenting ICI efficacy[167,168]. Additionally, tumor vaccines represent a promising modality for enhancing tumor-specific immune responses through targeted delivery of tumor antigens, offering a new avenue to combat ICI resistance[169]. For instance, DC vaccines and peptide vaccines targeting alpha-fetoprotein (AFP) or glypican-3 (GPC-3) have demonstrated acceptable safety profiles in HCC patients[170]. Furthermore, precision or personalized immunotherapy, in which regimens are tailored to individual tumor biology and host characteristics, offers a compelling avenue to maximize therapeutic impact.

Predictive biomarkers are indispensable for guiding ICI therapy, enabling identification of likely responders, monitoring therapeutic efficacy, assessing recurrence risk, and anticipating irAEs, thereby advancing precision immunotherapy for HCC. Currently, biomarkers under investigation encompass host-related factors (e.g., AFP, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, gut microbiota), and tumor-derived markers [e.g., PD-L1 expression, TMB, microsatellite instability, circulating tumor DNA (ctDNA), tumor-infiltrating lymphocytes, and driver gene mutations [e.g., tumor protein p53 (TP53)][171-173]. Although most remain in the investigational phase and are not yet embedded in routine clinical workflows, these markers have considerably deepened our understanding of ICI responsiveness and hold substantial potential for future integration into clinical practice.

 DECLARATIONS Acknowledgment

The Graphical Abstract was created with BioRender. H, T. (2025) https://BioRender.com/96dg8hw.

 Authors’ contributions

Conception, design, and editing of the manuscript: Zhao Q

Collection and interpretation of data, writing the initial draft: Zhang L, He T

Drawing figures: He T

 Availability of data and materials

Not applicable.

 AI and AI-assisted tools statement

During the preparation of this manuscript, the AI tool DeepSeek (web version) was used solely for language editing. The tool did not influence the study design, data collection, analysis, interpretation, or the scientific content of the work. All authors take full responsibility for the accuracy, integrity, and final content of the manuscript.

 Financial support and sponsorship

None.

 Conflicts of interest

All authors declared that there are no conflicts of interest.

 Ethical approval and consent to participate

Not applicable.

 Consent for publication

Not applicable.

 Copyright

© The Author(s) 2026.

 Kim E Viatour P Hepatocellular carcinoma: old friends and new tricks Exp Mol Med 2020 52 1898 907 10.1038/s12276-020-00527-1 33268834 PMC8080814 Bray F Laversanne M Sung H Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2024 74 229 63 10.3322/caac.21834 38572751 Brown ZJ Tsilimigras DI Ruff SM Management of hepatocellular carcinoma: a review JAMA Surg 2023 158 410 20 10.1001/jamasurg.2022.7989 36790767 Ju MR Yopp AC Surgical resection of early stage hepatocellular carcinoma: balancing tumor biology with the host liver Chin Clin Oncol 2021 10 5 10.21037/cco-20-130 32434346 Feng S Roll GR Rouhani FJ Sanchez Fueyo A The future of liver transplantation Hepatology 2024 80 674 97 10.1097/hep.0000000000000873 38537154 Yang GY He ZW Tang YC Unraveling the efficacy network: a network meta-analysis of adjuvant external beam radiation therapy methods after hepatectomy World J Gastrointest Surg 2024 16 205 14 10.4240/wjgs.v16.i1.205 38328333 PMC10845281 Wang Y Deng B Hepatocellular carcinoma: molecular mechanism, targeted therapy, and biomarkers Cancer Metastasis Rev 2023 42 629 52 10.1007/s10555-023-10084-4 36729264 Liang X Gao H Xiao J Abrine, an IDO1 inhibitor, suppresses the immune escape and enhances the immunotherapy of anti-PD-1 antibody in hepatocellular carcinoma Front Immunol 2023 14 1185985 10.3389/fimmu.2023.1185985 37334368 PMC10272936 Cao D Chen MK Zhang QF Identification of immunological subtypes of hepatocellular carcinoma with expression profiling of immune-modulating genes Aging 2020 12 12187 205 10.18632/aging.103395 32544882 PMC7343492 Zhao Q Huang ZL He M Gao Z Kuang DM BTLA identifies dysfunctional PD-1-expressing CD4+ T cells in human hepatocellular carcinoma Oncoimmunology 2016 5 e1254855 10.1080/2162402x.2016.1254855 28123898 PMC5214739 Zhang M Pang HJ Zhao W VISTA expression associated with CD8 confers a favorable immune microenvironment and better overall survival in hepatocellular carcinoma BMC Cancer 2018 18 511 10.1186/s12885-018-4435-1 29720116 PMC5932869 Chiu DK Yuen VW Cheu JW Hepatocellular carcinoma cells up-regulate PVRL1, stabilizing PVR and inhibiting the cytotoxic T-cell response via TIGIT to mediate tumor resistance to PD1 inhibitors in mice Gastroenterology 2020 159 609 23 10.1053/j.gastro.2020.03.074 32275969 Cheung CCL Seah YHJ Fang J Immunohistochemical scoring of LAG-3 in conjunction with CD8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma Front Immunol 2023 14 1150985 10.3389/fimmu.2023.1150985 37342338 PMC10277502 Tang Z Wang W Gao B Unveiling Tim-3 immune checkpoint expression in hepatocellular carcinoma through abdominal contrast-enhanced CT habitat radiomics Front Oncol 2024 14 1456748 10.3389/fonc.2024.1456748 39582537 PMC11581969 Pinter M Jain RK Duda DG The current landscape of immune checkpoint blockade in hepatocellular carcinoma: a review JAMA Oncol 2021 7 113 23 10.1001/jamaoncol.2020.3381 33090190 PMC8265820 Yu W He J Wang F NR4A1 mediates NK-cell dysfunction in hepatocellular carcinoma via the IFN-γ/p-STAT1/IRF1 pathway Immunology 2023 169 69 82 10.1111/imm.13611 36420610 Yuen VW Chiu DK Law CT Using mouse liver cancer models based on somatic genome editing to predict immune checkpoint inhibitor responses J Hepatol 2023 78 376 89 10.1016/j.jhep.2022.10.037 36455783 Bonaventura P Shekarian T Alcazer V Cold tumors: a therapeutic challenge for immunotherapy Front Immunol 2019 10 168 10.3389/fimmu.2019.00168 30800125 PMC6376112 Lurje I Hammerich L Tacke F Dendritic cell and t cell crosstalk in liver fibrogenesis and hepatocarcinogenesis: implications for prevention and therapy of liver cancer Int J Mol Sci 2020 21 7378 10.3390/ijms21197378 33036244 PMC7583774 Han Y Chen Z Yang Y Human CD14+ CTLA-4+ regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2,3-dioxygenase production in hepatocellular carcinoma Hepatology 2014 59 567 79 10.1002/hep.26694 23960017 Xiao R Tian Y Zhang J Increased Siglec-9/Siglec-9L interactions on NK cells predict poor HCC prognosis and present a targetable checkpoint for immunotherapy J Hepatol 2024 80 792 804 10.1016/j.jhep.2024.01.028 38331327 Wei H Suo C Gu X AKR1D1 suppresses liver cancer progression by promoting bile acid metabolism-mediated NK cell cytotoxicity Cell Metab 2025 37 1103 18.e7 10.1016/j.cmet.2025.01.011 40010348 Prawira A Xu H Mei Y Targeting Treg-fibroblast interaction to enhance immunotherapy in steatotic liver disease-related hepatocellular carcinoma Gut 2025 75 105 18 10.1136/gutjnl-2025-335084 40695620 PMC12703262 Suthen S Lim CJ Nguyen PHD Hypoxia-driven immunosuppression by Treg and type-2 conventional dendritic cells in HCC Hepatology 2022 76 1329 44 10.1002/hep.32419 35184329 Cheng K Cai N Yang X Short-term starvation boosts anti-PD-L1 therapy by reshaping tumor-associated macrophages in hepatocellular carcinoma Hepatology 2025 82 1414 31 10.1097/hep.0000000000001244 39879585 PMC12614376 Tang B Zhu J Wang Y Targeted xCT-mediated ferroptosis and protumoral polarization of macrophages is effective against HCC and enhances the efficacy of the anti-PD-1/L1 response Adv Sci 2023 10 e2203973 10.1002/advs.202203973 36442849 PMC9839855 Zhang Y Rao Y Lu J The influence of biophysical niche on tumor-associated macrophages in liver cancer Hepatol Commun 2024 8 e0569 10.1097/hc9.0000000000000569 39470328 PMC11524744 Ning J Ye Y Shen H Macrophage-coated tumor cluster aggravates hepatoma invasion and immunotherapy resistance via generating local immune deprivation Cell Rep Med 2024 5 101505 10.1016/j.xcrm.2024.101505 38614095 PMC11148514 Xie P Yu M Zhang B CRKL dictates anti-PD-1 resistance by mediating tumor-associated neutrophil infiltration in hepatocellular carcinoma J Hepatol 2024 81 93 107 10.1016/j.jhep.2024.02.009 38403027 Sangro B Sarobe P Hervás-Stubbs S Melero I Advances in immunotherapy for hepatocellular carcinoma Nat Rev Gastroenterol Hepatol 2021 18 525 43 10.1038/s41575-021-00438-0 33850328 PMC8042636 Park D Sahai E Rullan A SnapShot: cancer-associated fibroblasts Cell 2020 181 486 e1 10.1016/j.cell.2020.03.013 32302576 Kato T Noma K Ohara T Cancer-associated fibroblasts affect intratumoral CD8+ and FoxP3+ T cells via IL6 in the tumor microenvironment Clin Cancer Res 2018 24 4820 33 10.1158/1078-0432.ccr-18-0205 29921731 Yang X Lin Y Shi Y FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling Cancer Res 2016 76 4124 35 10.1158/0008-5472.can-15-2973 27216177 Timperi E Romano E Stromal circuits involving tumor-associated macrophages and cancer-associated fibroblasts Front Immunol 2023 14 1194642 10.3389/fimmu.2023.1194642 37342322 PMC10277481 Han S Bao X Zou Y d-lactate modulates M2 tumor-associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma Sci Adv 2023 9 eadg2697 10.1126/sciadv.adg2697 37467325 PMC10355835 Shen XT Xie SZ Zheng X Cirrhotic-extracellular matrix attenuates aPD-1 treatment response by initiating immunosuppressive neutrophil extracellular traps formation in hepatocellular carcinoma Exp Hematol Oncol 2024 13 20 10.1186/s40164-024-00476-9 38388466 PMC10882882 Zeng W Liu F Liu Y Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma Clin Mol Hepatol 2025 31 489 508 10.3350/cmh.2024.0934 39736265 PMC12016601 Wu B Wang Q Li B Jiang M LAMTOR1 degrades MHC-II via the endocytic in hepatocellular carcinoma Carcinogenesis 2022 43 1059 70 10.1093/carcin/bgac075 36070764 PMC9890926 Wang Z Wang Y Gao P Ding J Immune checkpoint inhibitor resistance in hepatocellular carcinoma Cancer Lett 2023 555 216038 10.1016/j.canlet.2022.216038 36529238 Chan TA Yarchoan M Jaffee E Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic Ann Oncol 2019 30 44 56 10.1093/annonc/mdy495 30395155 PMC6336005 Xie Q Zhang P Wang Y Mei W Zeng C Overcoming resistance to immune checkpoint inhibitors in hepatocellular carcinoma: Challenges and opportunities Front Oncol 2022 12 958720 10.3389/fonc.2022.958720 36119533 PMC9478417 Zhou Z Yu X Chen Y Inhibition of the B7-H3 immune checkpoint limits hepatocellular carcinoma progression by enhancing T lymphocyte-mediated immune cytotoxicity in vitro and in vivo Clin Transl Oncol 2023 25 1067 79 10.1007/s12094-022-03013-4 36512305 Shrestha R Bridle KR Crawford DHG Jayachandran A Immune checkpoint molecules are regulated by transforming growth factor (TGF)-β1-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma Int J Med Sci 2021 18 2466 79 10.7150/ijms.54239 34104078 PMC817617 David CJ Massagué J Contextual determinants of TGFβ action in development, immunity and cancer Nat Rev Mol Cell Biol 2018 19 419 35 10.1038/s41580-018-0007-0 29643418 PMC7457231 Park BV Freeman ZT Ghasemzadeh A TGFβ1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer Cancer Discov 2016 6 1366 81 10.1158/2159-8290.cd-15-1347 27683557 PMC5295786 Chen J Gingold JA Su X Immunomodulatory TGF-β signaling in hepatocellular carcinoma Trends Mol Med 2019 25 1010 23 10.1016/j.molmed.2019.06.007 31353124 de Gramont A, Faivre S, Raymond E. Novel TGF-β inhibitors ready for prime time in onco-immunology Oncoimmunology 2017 6 e1257453 10.1080/2162402x.2016.1257453 28197376 PMC5283641 Rebouissou S Franconi A Calderaro J Genotype-phenotype correlation of CTNNB1 mutations reveals different ß-catenin activity associated with liver tumor progression Hepatology 2016 64 2047 61 10.1002/hep.28638 27177928 Ruiz de Galarreta M Bresnahan E Molina-Sánchez P β-Catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma Cancer Discov 2019 9 1124 41 10.1158/2159-8290.cd-19-0074 31186238 PMC6677618 Lehrich BM Delgado ER Yasaka TM Precision targeting of β-catenin induces tumor reprogramming and immunity in hepatocellular cancers Nat Commun 2025 16 5009 10.1038/s41467-025-60457-2 40442146 PMC12122713 Liu Z Ning F Cai Y The EGFR-P38 MAPK axis up-regulates PD-L1 through miR-675-5p and down-regulates HLA-ABC via hexokinase-2 in hepatocellular carcinoma cells Cancer Commun 2021 41 62 78 10.1002/cac2.12117 34236149 PMC7819566 Xing S Chen S Yang X Huang W Role of MAPK activity in PD-L1 expression in hepatocellular carcinoma cells J buon 2020 25 1875 82 33099927 Chen Y Liu YC Sung YC Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors Sci Rep 2017 7 44123 10.1038/srep44123 28276530 PMC5343435 Lin Z Huang L Li SL Gu J Cui X Zhou Y PTEN loss correlates with T cell exclusion across human cancers BMC Cancer 2021 21 429 10.1186/s12885-021-08114-x 33874915 PMC8054401 Vidotto T Melo CM Castelli E Koti M Dos Reis RB Squire JA Emerging role of PTEN loss in evasion of the immune response to tumours Br J Cancer 2020 122 1732 43 10.1038/s41416-020-0834-6 32327707 PMC7283470 Zhang S Gan X Qiu J IL-10 derived from Hepatocarcinoma cells improves human induced regulatory T cells function via JAK1/STAT5 pathway in tumor microenvironment Mol Immunol 2021 133 163 72 10.1016/j.molimm.2021.02.014 33667986 Fernandez-Barrena MG Uriarte I Sarobe P Avila MA Epigenetic mechanisms in HCC immune landscape: therapeutic implications Semin Immunol 2025 79 101980 10.1016/j.smim.2025.101980 40737838 Tong Y Chen Z Wu J METTL3 promotes an immunosuppressive microenvironment in bladder cancer via m6A-dependent CXCL5/CCL5 regulation J Immunother Cancer 2025 13 e011108 10.1136/jitc-2024-011108 40234090 PMC12001370 Wang DX Long JY Li RZ Mutation status of the KMT2 family associated with immune checkpoint inhibitors (ICIs) therapy and implicating diverse tumor microenvironments Mol Cancer 2024 23 15 10.1186/s12943-023-01930-8 38225603 PMC10789049 Jiang Y Yu Z Wang J Targeting USP47 enhances immunotherapy in hepatocellular carcinoma by destabilizing PD-L1 Int Immunopharmacol 2025 161 115024 10.1016/j.intimp.2025.115024 40494207 Gao Y Nihira NT Bu X Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy Nat Cell Biol 2020 22 1064 75 10.1038/s41556-020-0562-4 32839551 PMC7484128 Lin M He J Zhang X Targeting fibrinogen-like protein 1 enhances immunotherapy in hepatocellular carcinoma J Clin Invest 2023 133 e164528 10.1172/jci164528 37115693 PMC10145938 Tu Y Wu H Zhong C Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma Gut 2025 74 613 27 10.1136/gutjnl-2024-332281 39486886 PMC12013592 Zeng C Ye S Chen Y HOXA-AS3 promotes proliferation and migration of hepatocellular carcinoma cells via the miR-455-5p/PD-L1 axis J Immunol Res 2021 2021 9289719 10.1155/2021/9289719 34988230 PMC8723882 Zhang X Pan B Qiu J lncRNA MIAT targets miR-411-5p/STAT3/PD-L1 axis mediating hepatocellular carcinoma immune response Int J Exp Pathol 2022 103 102 11 10.1111/iep.12440 35429078 PMC9107606 Peng X He Z Yuan D Liu Z Rong P Lactic acid: the culprit behind the immunosuppressive microenvironment in hepatocellular carcinoma Biochim Biophys Acta Rev Cancer 2024 1879 189164 10.1016/j.bbcan.2024.189164 39096976 Fu J Zhang Z Zhou L Impairment of CD4+ cytotoxic T cells predicts poor survival and high recurrence rates in patients with hepatocellular carcinoma Hepatology 2013 58 139 49 10.1002/hep.26054 22961630 Tang W Zhou J Yang W Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver Cell Mol Immunol 2022 19 834 47 10.1038/s41423-022-00872-3 35595819 PMC9243114 Qin WH Yang ZS Li M High serum levels of cholesterol increase antitumor functions of nature killer cells and reduce growth of liver tumors in mice Gastroenterology 2020 158 1713 27 10.1053/j.gastro.2020.01.028 31972238 Tu X Lin W Zhai X Oleanolic acid inhibits M2 macrophage polarization and potentiates anti-PD-1 therapy in hepatocellular carcinoma by targeting miR-130b-3p-PTEN-PI3K-Akt signaling and glycolysis Phytomedicine 2025 141 156750 10.1016/j.phymed.2025.156750 40250003 Bai J Tang R Zhou K An asparagine metabolism-based classification reveals the metabolic and immune heterogeneity of hepatocellular carcinoma BMC Med Genomics 2022 15 222 10.1186/s12920-022-01380-z 36284275 PMC9594908 Chen J Wang R Liu Z Unbalanced glutamine partitioning between CD8T cells and cancer cells accompanied by immune cell dysfunction in hepatocellular carcinoma Cells 2022 11 3924 10.3390/cells11233924 36497182 PMC9739589 Sun C Wang B Hao S Adenosine-A2A receptor pathway in cancer immunotherapy Front Immunol 2022 13 837230 10.3389/fimmu.2022.837230 35386701 PMC8977492 Hu Z Chen G Zhao Y Exosome-derived circCCAR1 promotes CD8 + T-cell dysfunction and anti-PD1 resistance in hepatocellular carcinoma Mol Cancer 2023 22 55 10.1186/s12943-023-01759-1 36932387 PMC10024440 Zhang PF Gao C Huang XY Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma Mol Cancer 2020 19 110 10.1186/s12943-020-01222-5 32593303 PMC7320583 Yang Y Wu T Wang Y Hypoxic tumour-derived exosomal miR-1290 exacerbates the suppression of CD8+ T cells by promoting M2 macrophage polarization Immunology 2024 173 672 88 10.1111/imm.13853 39183579 Chen J Lin Z Liu L GOLM1 exacerbates CD8+ T cell suppression in hepatocellular carcinoma by promoting exosomal PD-L1 transport into tumor-associated macrophages Signal Transduct Target Ther 2021 6 397 10.1038/s41392-021-00784-0 34795203 PMC8602261 Kou L Xie X Chen X Li B Li J Li Y The progress of research on immune checkpoint inhibitor resistance and reversal strategies for hepatocellular carcinoma Cancer Immunol Immunother 2023 72 3953 69 10.1007/s00262-023-03568-3 37917364 PMC10992589 Ruff SM Manne A Cloyd JM Dillhoff M Ejaz A Pawlik TM Current landscape of immune checkpoint inhibitor therapy for hepatocellular carcinoma Curr Oncol 2023 30 5863 75 10.3390/curroncol30060439 37366922 PMC10297531 Kaseb A, Vence L, Blando J, et al. PD-009 - Randomized, open-label, perioperative phase II study evaluating nivolumab alone versus nivolumab plus ipilimumab in patients with resectable HCC. Ann Oncol. 2019;30:iv112. Available from: https://www.annalsofoncology.org/article/S0923-7534(19)30920-2/fulltext. [Last accessed on 14 May 2026]. Sangro B Yau T Harding JJ RELATIVITY-106: a phase 1/2 trial of nivolumab (NIVO) + relatlimab (RELA) in combination with bevacizumab (BEV) in first-line (1L) hepatocellular carcinoma (HCC) JCO 2023 41 TPS636 10.1200/jco.2023.41.4_suppl.tps636 Yau T, Galle PR, Decaens T, et al.; CheckMate 9DW investigators. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial. Lancet. 2025;405:1851-64. 10.1016/s0140-6736(25)00403-9 Yarchoan M Zhu Q Durham JN Feasibility and efficacy of neoadjuvant cabozantinib and nivolumab in patients with borderline resectable or locally advanced hepatocellular carcinoma (HCC) JCO 2021 39 335 10.1200/jco.2021.39.3_suppl.335 Llovet JM Kudo M Cheng A Lenvatinib (len) plus pembrolizumab (pembro) for the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC): phase 3 LEAP-002 study JCO 2019 37 TPS4152 10.1200/jco.2019.37.15_suppl.tps4152 El-khoueiry AB Llovet JM Vogel A LEAP-012 trial in progress: transarterial chemoembolization (TACE) with or without lenvatinib plus pembrolizumab for intermediate-stage hepatocellular carcinoma (HCC) JCO 2022 40 TPS494 10.1200/jco.2022.40.4_suppl.tps494 Galle P Kim R Sung M 990P Updated results of a phase Ib study of regorafenib (REG) plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC) Ann Oncol 2020 31 S691 2 10.1016/j.annonc.2020.08.1106 Xia Y Wang P Pu L Preliminary efficacy and safety of perioperative treatment of camrelizumab combined with apatinib in resectable hepatocellular carcinoma (HCC): a prospective phase II study JCO 2021 39 4082 10.1200/jco.2021.39.15_suppl.4082 Zhu H Teng G Fan W Transarterial chemoembolization (TACE) combined with camrelizumab and apatinib versus TACE alone in the treatment of unresectable hepatocellular carcinoma eligible for embolization: a multicenter, open-label, randomized, phase 2 study (CAP-ACE) JCO 2025 43 LBA522 10.1200/jco.2025.43.4_suppl.lba522 Ren Z, Xu J, Bai Y, et al.; ORIENT-32 study group. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol. 2021;22:977-90. 10.1016/s1470-2045(21)00252-7 34143971 Zhou J Shi Y Liu B A phase Ib, multicenter, open-label study to assess the safety, tolerability, and preliminary efficacy of sintilimab plus IBI310 (anti-CTLA4 mAb) in patients with advanced hepatocellular carcinoma JCO 2022 40 421 10.1200/jco.2022.40.4_suppl.421 Sun HC Zhu XD Wang ZY Sintilimab plus bevacizumab followed by resection in intermediate-stage hepatocellular carcinoma: a phase Ib clinical trial with biomarker analysis BMJ Oncol 2024 3 e000578 10.1136/bmjonc-2024-000578 40046248 PMC11880783 Zhou J, Bai L, Luo J, et al.; APOLLO Study Group. Anlotinib plus penpulimab versus sorafenib in the first-line treatment of unresectable hepatocellular carcinoma (APOLLO): a randomised, controlled, phase 3 trial. Lancet Oncol. 2025;26:719-31. 10.1016/s1470-2045(25)00190-1 40349716 Sangro B, Chan SL, Kelley RK, et al.; HIMALAYA investigators. Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Ann Oncol. 2024;35:448-57. 10.1016/j.annonc.2024.02.005 38382875 Lim HY Heo J Kim T Safety and efficacy of durvalumab plus bevacizumab in unresectable hepatocellular carcinoma: results from the phase 2 study 22 (NCT02519348) JCO 2022 40 436 436 10.1200/jco.2022.40.4_suppl.436 Heo J Okusaka T Yoon J Outcomes by transarterial chemoembolization (TACE) modality from participants (pts) with embolization-eligible hepatocellular carcinoma (HCC) treated with durvalumab (D) + bevacizumab (B) + TACE and placebos (PBO) + TACE: EMERALD-1 subgroup analysis JCO 2025 43 575 10.1200/jco.2025.43.4_suppl.575 Finn RS, Qin S, Ikeda M, et al.; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894-905. 10.1056/nejmoa1915745 32402160 Stein S Cheng W Wiess C Atezolizumab and bevacizumab in combination with TACE for patients with BCLC B HCC JCO 2024 42 TPS584 10.1200/jco.2024.42.3_suppl.tps584 Rimassa L Cheng A Braiteh F Phase 3 (COSMIC-312) study of cabozantinib in combination with atezolizumab vs sorafenib in patients with advanced hepatocellular carcinoma (aHCC) who have not received previous systemic anticancer therapy Ann Oncol 2019 30 iv65 6 10.1093/annonc/mdz155.237 Acoba JD Fukaya E Goodyear SM Kardosh A Cobolimab and dostarlimab in the first-line treatment of unresectable hepatoma: a multi-center, single arm, phase 2 trial JCO 2025 43 4099 4099 10.1200/jco.2025.43.16_suppl.4099 Kato Y Tabata K Kimura T Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway PLoS One 2019 14 e0212513 10.1371/journal.pone.0212513 30811474 PMC6392299 Kimura T Kato Y Ozawa Y Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model Cancer Sci 2018 109 3993 4002 10.1111/cas.13806 30447042 PMC6272102 Abou-Elkacem L Arns S Brix G Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model Mol Cancer Ther 2013 12 1322 31 10.1158/1535-7163.mct-12-1162 23619301 Kwilas AR Ardiani A Donahue RN Aftab DT Hodge JW Dual effects of a targeted small-molecule inhibitor (cabozantinib) on immune-mediated killing of tumor cells and immune tumor microenvironment permissiveness when combined with a cancer vaccine J Transl Med 2014 12 294 10.1186/s12967-014-0294-y 25388653 PMC4236498 Zhu XD Huang C Shen YH Downstaging and resection of initially unresectable hepatocellular carcinoma with tyrosine kinase inhibitor and anti-PD-1 antibody combinations Liver Cancer 2021 10 320 9 10.1159/000514313 34414120 PMC8339461 Killock D Novel ICI-TKI combination improves HCC outcomes Nat Rev Clin Oncol 2023 20 733 10.1038/s41571-023-00812-8 37563429 Xu Y Fu S Shang K Zeng J Mao Y PD-1 inhibitors plus lenvatinib versus PD-1 inhibitors plus regorafenib in patients with advanced hepatocellular carcinoma after failure of sorafenib Front Oncol 2022 12 958869 10.3389/fonc.2022.958869 36176403 PMC9513444 Liu JKH Irvine AF Jones RL Samson A Immunotherapies for hepatocellular carcinoma Cancer Med 2022 11 571 91 10.1002/cam4.4468 34953051 PMC8817091 Kudo M Scientific rationale for combined immunotherapy with PD-1/PD-L1 antibodies and VEGF inhibitors in advanced hepatocellular carcinoma Cancers 2020 12 1089 10.3390/cancers12051089 32349374 PMC7281246 Finn RS, Qin S, Ikeda M, et al.; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894-905. 10.1016/s1470-2045(20)30156-x 32502443 Qin S, Chan SL, Gu S, et al.; CARES-310 Study Group. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023;402:1133-46. 10.1159/000551156 37499670 Holmgaard RB Schaer DA Li Y Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade J Immunother Cancer 2018 6 47 10.1186/s40425-018-0356-4 Xiong Z Chan SL Zhou J Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma Gut 2023 72 1758 73 10.1136/gutjnl-2022-328364 37019619 PMC10423534 Yang C Tao T Wu Y Wang W Liu S Research advances in immunotherapy combined with DNA damage response inhibitors for liver cancer therapy J Cancer Metastasis Treat 2024 10 14 10.20517/2394-4722.2023.175 Cheng B Pan W Xing Y Xiao Y Chen J Xu Z Recent advances in DDR (DNA damage response) inhibitors for cancer therapy Eur J Med Chem 2022 230 114109 10.1016/j.ejmech.2022.114109 35051747 Shi C Qin K Lin A The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy J Exp Clin Cancer Res 2022 41 268 10.1186/s13046-022-02469-0 36071479 PMC9450390 Hsiehchen D Beg MS Kainthla R The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial Nat Commun 2024 15 2178 10.1038/s41467-024-46542-y 38467639 PMC10928173 Zhu Y Chen M Xu D The combination of PD-1 blockade with interferon-α has a synergistic effect on hepatocellular carcinoma Cell Mol Immunol 2022 19 726 37 10.1038/s41423-022-00848-3 35459855 PMC9151669 Yang W Feng Y Zhou J A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma Sci Transl Med 2021 13 eaaz6804 10.1126/scitranslmed.aaz6804 33827976 Liu H Zeng X Ren X Targeting tumour-intrinsic N(7)-methylguanosine tRNA modification inhibits MDSC recruitment and improves anti-PD-1 efficacy Gut 2023 72 1555 67 10.1136/gutjnl-2022-327230 36283801 Ning WR Jiang D Liu XC Carbonic anhydrase XII mediates the survival and prometastatic functions of macrophages in human hepatocellular carcinoma J Clin Invest 2022 132 e153110 10.1172/jci153110 35362480 PMC8970669 Kaseb AO, Tran Cao HS, Mohamed YI, et al.; Kaseb’s. Final results of a randomized, open label, perioperative phase II study evaluating nivolumab alone or nivolumab plus ipilimumab in patients with resectable HCC. JCO. 2020;38:4599. 10.1200/jco.2020.38.15_suppl.4599 Abou-alfa GK, Sangro B, Morse M, et al.; 022 Study Group. Phase 1/2 study of durvalumab and tremelimumab as monotherapy and in combination in patients with unresectable hepatocellular carcinoma (HCC). JCO. 2016;34:TPS3103. 10.1200/jco.2016.34.15_suppl.tps3103 Rimassa L Chan SL Sangro B Five-year overall survival update from the HIMALAYA study of tremelimumab plus durvalumab in unresectable HCC J Hepatol 2025 83 899 908 10.1016/j.jhep.2025.03.033 40222621 Duan J Cui L Wang G Immunotherapy efficacy and safety of programmed cell death 1 (PD-1) versus programmed death ligand-1 (PD-L1) inhibitors in pan-cancer: a systematic review and meta-analysis JCO 2019 37 e14113 10.1200/jco.2019.37.15_suppl.e14113 Chan SL Tan BR Jimenez E AMBER part 2F: cobolimab in combination with dostarlimab in treatment-naïve patients with locally advanced/metastatic and/or unresectable hepatocellular carcinoma (HCC) JCO 2025 43 TPS650 10.1200/jco.2025.43.4_suppl.tps650 Qin S Xu L Yi M Yu S Wu K Luo S Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4 Mol Cancer 2019 18 155 10.1186/s12943-019-1091-2 31690319 PMC6833286 Leone P Solimando AG Fasano R The evolving role of immune checkpoint inhibitors in hepatocellular carcinoma treatment Vaccines 2021 9 532 10.3390/vaccines9050532 34065489 PMC8160723 Tamai Y Fujiwara N Tanaka T Mizuno S Nakagawa H Combination therapy of immune checkpoint inhibitors with locoregional therapy for hepatocellular carcinoma Cancers 2023 15 5072 10.3390/cancers15205072 37894439 PMC10605879 Brandi N Renzulli M The synergistic effect of interventional locoregional treatments and immunotherapy for the treatment of hepatocellular carcinoma Int J Mol Sci 2023 24 8598 10.3390/ijms24108598 37239941 PMC10217839 Greten TF Mauda-Havakuk M Heinrich B Korangy F Wood BJ Combined locoregional-immunotherapy for liver cancer J Hepatol 2019 70 999 1007 10.1016/j.jhep.2019.01.027 30738077 PMC6462230 Kudo M, Ren Z, Guo Y, et al.; LEAP-012 investigators. Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): a multicentre, randomised, double-blind, phase 3 study. Lancet. 2025;405:203-15. 10.1016/s0140-6736(24)02575-3 39798578 Xue M Wu Y Tang Y Efficacy and safety of TACE combined with lenvatinib and PD-1 Inhibitor in intermediate-stage HCC exceeding the up-7 criteria: a retrospective cohort study Front Immunol 2025 16 1560750 10.3389/fimmu.2025.1560750 40574843 PMC12197949 Chen J Hu C Chen Y Lee Y Wang C Lee Y Tu1536: hepatic arterial infusion chemotherapy (HAIC) with targeted agents and immune checkpoint inhibitors (ICIs) in advanced hepatocellular carcinoma (HCC): systematic review and meta-analysis Gastroenterology 2025 169 S 1446 10.1016/s0016-5085(25)04215-5 Yunxiuxiu X Peng L Chen Y Apatinib and camrelizumab plus Intravenous FOLFOX or hepatic arterial infusion chemotherapy with FOLFOX for advanced HCC: a multicenter, prospective, randomized phase III trial JCO 2024 42 TPS4193 10.1200/jco.2024.42.16_suppl.tps4193 Shannon AH Manne A Diaz Pardo DA Pawlik TM Combined radiotherapy and immune checkpoint inhibition for the treatment of advanced hepatocellular carcinoma Front Oncol 2023 13 1193762 10.3389/fonc.2023.1193762 37554167 PMC10405730 Iyer RV Petroziello M Parikh N A phase II study of atezolizumab (ATEZO) and bevacizumab (BEV) in combination with Y90 TARE in patients (pts) with hepatocellular carcinoma (HCC): Y90+/- BEAT JCO 2023 41 TPS629 10.1200/jco.2023.41.4_suppl.tps629 Li H You J Wei Y Huaier improves the efficacy of anti-PD-L1 Ab in the treatment of hepatocellular carcinoma by regulating tumor immune microenvironment Phytomedicine 2024 123 155189 10.1016/j.phymed.2023.155189 37984124 Cao M Yan H Han X Ginseng-derived nanoparticles alter macrophage polarization to inhibit melanoma growth J Immunother Cancer 2019 7 326 10.1186/s40425-019-0817-4 31775862 PMC6882204 Yu Z Li Y Li Y Bufalin stimulates antitumor immune response by driving tumor-infiltrating macrophage toward M1 phenotype in hepatocellular carcinoma J Immunother Cancer 2022 10 e004297 10.1136/jitc-2021-004297 35618286 PMC9125767 Guo L Li H Fan T Ma Y Wang L Synergistic efficacy of curcumin and anti-programmed cell death-1 in hepatocellular carcinoma Life Sci 2021 279 119359 10.1016/j.lfs.2021.119359 33753114 Ke M Zhang Z Xu B Baicalein and baicalin promote antitumor immunity by suppressing PD-L1 expression in hepatocellular carcinoma cells Int Immunopharmacol 2019 75 105824 10.1016/j.intimp.2019.105824 31437792 Cai S Gou Y Chen Y Luteolin exerts anti-tumour immunity in hepatocellular carcinoma by accelerating CD8+ T lymphocyte infiltration J Cell Mol Med 2024 28 e18535 10.1111/jcmm.18535 39267250 PMC11392827 Zhang L Jiang G Yao F Osthole promotes anti-tumor immune responses in tumor-bearing mice with hepatocellular carcinoma Immunopharmacol Immunotoxicol 2015 37 301 7 10.3109/08923973.2015.1035391 25975579 Yang X Lam W Jiang Z YIV-906 potentiated anti-PD1 action against hepatocellular carcinoma by enhancing adaptive and innate immunity in the tumor microenvironment Sci Rep 2021 11 13482 10.1038/s41598-021-91623-3 34188068 PMC8242098 Yu YX Wang S Liu ZN Traditional Chinese medicine in the era of immune checkpoint inhibitor: theory, development, and future directions Chin Med 2023 18 59 10.1186/s13020-023-00751-7 37210537 PMC10199665 Mo Z Cao Z Yu L An integrative analysis reveals the potential mechanism between herbal medicine yinchen and immunoregulation in hepatocellular carcinoma Biomed Res Int 2020 2020 8886914 10.1155/2020/8886914 33457419 PMC7785361 Xie Y Yan F Wang X Mechanisms and network pharmacological analysis of Yangyin Fuzheng Jiedu prescription in the treatment of hepatocellular carcinoma Cancer Med 2023 12 3237 59 10.1002/cam4.5064 36043445 PMC9939140 Yan F Wang X Xie Y Yangyin Fuzheng Jiedu Prescription exerts anti-tumor immunity in hepatocellular carcinoma by alleviating exhausted T cells Phytomedicine 2021 91 153722 10.1016/j.phymed.2021.153722 34488188 Wu XQ Ying F Chung KPS Intestinal Akkermansia muciniphila complements the efficacy of PD1 therapy in MAFLD-related hepatocellular carcinoma Cell Rep Med 2025 6 101900 10.1016/j.xcrm.2024.101900 39798567 PMC11866522 Ren Z Li A Jiang J Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma Gut 2019 68 1014 23 10.1136/gutjnl-2017-315084 30045880 PMC6580753 Wu H Zheng X Pan T Dynamic microbiome and metabolome analyses reveal the interaction between gut microbiota and anti-PD-1 based immunotherapy in hepatocellular carcinoma Int J Cancer 2022 151 1321 34 10.1002/ijc.34118 35579980 Ponziani FR De Luca A Picca A Gut dysbiosis and fecal calprotectin predict response to immune checkpoint inhibitors in patients with hepatocellular carcinoma Hepatol Commun 2022 6 1492 501 10.1002/hep4.1905 35261212 PMC9134810 Sivan A Corrales L Hubert N Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy Science 2015 350 1084 9 10.1126/science.aac4255 26541606 PMC4873287 Vétizou M Pitt JM Daillère R Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota Science 2015 350 1079 84 10.1126/science.aad1329 26541610 PMC4721659 Lee PC Wu CJ Hung YW Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma J Immunother Cancer 2022 10 e004779 10.1136/jitc-2022-004779 35738801 PMC9226985 Yu J Zhu P Shi L Bifidobacterium longum promotes postoperative liver function recovery in patients with hepatocellular carcinoma Cell Host Microbe 2024 32 131 44.e6 10.1016/j.chom.2023.11.011 38091982 Russo E Fiorindi C Giudici F Amedei A Immunomodulation by probiotics and prebiotics in hepatocellular carcinoma World J Hepatol 2022 14 372 85 10.4254/wjh.v14.i2.372 35317185 PMC8891667 Rauber C Roberti MP Vehreschild MJ Protocol: faecal microbiota transfer in liver cancer to overcome resistance to atezolizumab/bevacizumab - a multicentre, randomised, placebo-controlled, double-blind phase II trial (the FLORA trial) BMJ Open 2025 15 e097802 10.1136/bmjopen-2024-097802 40930564 PMC12421604 Mao J Wang D Long J Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers J Immunother Cancer 2021 9 e003334 10.1136/jitc-2021-003334 34873013 PMC8650503 Ma C Awosika JA Monge C Altering the gut microbiome and tumor microenvironment in advanced liver cancer: a phase II study of nivolumab, tadalafil and oral vancomycin in patients with refractory primary hepatocellular carcinoma or liver dominant metastatic cancer from colorectal or pancreatic cancers Cancer Lett 2025 632 217975 10.1016/j.canlet.2025.217975 40789510 Xiao K Li K Xiao K Yang J Zhou L Gut microbiota and hepatocellular carcinoma: metabolic products and immunotherapy modulation Cancer Med 2025 14 e70914 10.1002/cam4.70914 40314129 PMC12046294 Xie D Liu Y Xu F Immune microenvironment and immunotherapy in hepatocellular carcinoma: mechanisms and advances Front Immunol 2025 16 1581098 10.3389/fimmu.2025.1581098 40242773 PMC12000014 Zhu W Fan C Zhao Y Liu Y Cheng Y Zhou W Breaking bottlenecks: the future of hepatocellular carcinoma clinical trials and therapeutic targets Hepatol Int 2025 19 888 902 10.1007/s12072-025-10799-2 40156659 Guan L Wu S Zhu Q GPC3-targeted CAR-M cells exhibit potent antitumor activity against hepatocellular carcinoma Biochem Biophys Rep 2024 39 101741 10.1016/j.bbrep.2024.101741 38881757 PMC11176667 Myojin Y McCallen JD Ma C Adenosine A2a receptor inhibition increases the anti-tumor efficacy of anti-PD1 treatment in murine hepatobiliary cancers JHEP Rep 2024 6 100959 10.1016/j.jhepr.2023.100959 38192537 PMC10772255 Zhang J Dong K Zhang X Li C Yu J Wang W Characteristics of lactate metabolism phenotype in hepatocellular carcinoma Sci Rep 2023 13 19674 10.1038/s41598-023-47065-0 37952028 PMC10640573 Hecht JR Chan A Martin M Phase Ib study of talimogene laherparepvec (T-VEC) injection into liver metastases (LMs) in combination with intravenous (IV) atezolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC) or colorectal cancer (CRC) JCO 2019 37 TPS725 10.1200/jco.2019.37.4_suppl.tps725 Heo J Reid T Ruo L Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer Nat Med 2013 19 329 36 10.1038/nm.3089 23396206 PMC4268543 Zhao J Chen Y Ding ZY Liu JY Safety and efficacy of therapeutic cancer vaccines alone or in combination with immune checkpoint inhibitors in cancer treatment Front Pharmacol 2019 10 1184 10.3389/fphar.2019.01184 31680963 PMC6798079 Zanotta S Galati D De Filippi R Pinto A Enhancing dendritic cell cancer vaccination: the synergy of immune checkpoint inhibitors in combined therapies Int J Mol Sci 2024 25 7509 10.3390/ijms25147509 39062753 PMC11277144 Greten TF Villanueva A Korangy F Biomarkers for immunotherapy of hepatocellular carcinoma Nat Rev Clin Oncol 2023 20 780 98 10.1038/s41571-023-00816-4 37726418 Chan YT Zhang C Wu J Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma Mol Cancer 2024 23 189 10.1186/s12943-024-02101-z 39242496 PMC11378508 Cheng M Zheng X Wei J Liu M Current state and challenges of emerging biomarkers for immunotherapy in hepatocellular carcinoma (Review) Exp Ther Med 2023 26 586 10.3892/etm.2023.12285 38023367 PMC10665984