Targeted agents, such as sorafenib and lenvatinib, exert their antitumor effects through inhibition of multiple tyrosine kinase receptors, most notably vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs), which play central roles in tumor angiogenesis, endothelial cell survival, and tumor cell proliferation^[9]. By interrupting these signaling pathways, targeted therapies impair the tumor’s ability to establish and maintain a functional vascular network, thereby limiting oxygen and nutrient delivery and suppressing tumor growth. In HCC, where tumor progression is highly dependent on aberrant angiogenesis, blockade of these pathways has proven particularly relevant.

Y-90 radioembolization further exploits this vascular dependence by delivering high-dose, localized radiation to the tumor microenvironment. Radiation-induced endothelial injury leads to microvascular thrombosis, vessel collapse, and regional ischemia, resulting in substantial tumor necrosis. However, this vascular disruption also creates a hypoxic microenvironment that activates hypoxia-inducible factors (HIFs), which in turn drive compensatory upregulation of pro-angiogenic mediators, most prominently vascular endothelial growth factor (VEGF)^[11]. This adaptive response promotes neovascularization, restoring blood flow to residual tumor cells and enabling regrowth. Such angiogenic rebound has historically limited the durability of tumor control following radiation-based therapies alone and represents a key mechanism of therapeutic resistance.

Combining Y-90 radioembolization with anti-angiogenic targeted agents may offer a biologically rational strategy to counteract this process. While Y-90 induces direct cytotoxicity and vascular destruction, concurrent or sequential inhibition of VEGFR and PDGFR would theoretically blunt the hypoxia-driven surge in angiogenic signaling, effectively suppressing rebound neovascularization. By preventing reconstitution of the tumor vasculature, targeted agents may prolong the ischemic and cytotoxic effects of radiation, thereby enhancing local tumor control. Systemic inhibition of angiogenic and proliferative pathways may also limit the growth of microscopic residual disease and distant metastases, further extending the therapeutic benefit beyond the treated hepatic territory.

This complementary interaction positions anti-angiogenic therapy as a critical modulator of radiation-induced tumor adaptation and may produce more durable disease control and improved clinical outcomes in patients with HCC.

ICIs targeting programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have revolutionized cancer therapy by restoring T-cell-mediated tumor killing^[12]. These agents essentially release the brakes on the immune system, allowing cytotoxic T-cells to recognize and eliminate tumor cells more effectively. Importantly, radiation delivered by Y-90 induces immunogenic cell death, characterized by the release of tumor-associated neoantigens. These neoantigens activate dendritic cells, which then prime and expand cytotoxic T-cell populations, effectively “vaccinating” the immune system against the tumor^[14]. This process can convert immunologically “cold” tumors, which are typically resistant to immunotherapy due to a lack of immune infiltration, into “hot” tumors that are more responsive to ICIs.

The integration of Y-90 radioembolization with ICIs has the potential to produce synergistic antitumor immunity. Radiation-induced immunogenic cell death enhances tumor antigen presentation and T-cell activation, while ICIs sustain and amplify the immune response by preventing T-cell exhaustion and inhibition. This combined approach may yield more durable clinical responses and improve long-term survival outcomes compared to either modality alone.

The Sorafenib in Advanced Hepatocellular Carcinoma (SORAMIC) trial is a multicenter randomized, open-label phase II trial that compared survival in patients with advanced HCC treated with sorafenib alone to those treated with Y-90 in addition to sorafenib. According to the most recent BCLC staging and treatment strategy guidelines, sorafenib is a first-line systemic treatment alternative for advanced-stage HCC when atezolizumab-bevacizumab or durvalumab-tremelimumab are not feasible^[10]. The study found no significant improvement in OS with the addition of Y-90 to sorafenib therapy. Specific subgroup analyses within this trial, however, did demonstrate statistically significant survival benefits with the addition of Y-90 to sorafenib therapy. For example, survival benefits were observed in patients without cirrhosis [Hazard ratio (HR), 0.46; 0.25-0.86; P = 0.02], in patients with cirrhosis of non-alcoholic etiology (HR 0.63; P = 0.012), and in patients aged 65 years or younger (HR 0.65; P = 0.05)^[31].

An important consideration is that this landmark trial compared combination therapy with targeted monotherapy, rather than addressing this review’s focus on how combination therapy may be superior to SIRT monotherapy. Moreover, a post-hoc analysis of the SORAMIC trial assessed the follow-up images of 177 patients by mRECIST (modified Response Evaluation Criteria in Solid Tumors) and demonstrated a significantly increased objective response rate (ORR), complete response rate, and disease control rate among patients treated with combination therapy^[32].

The SARAH (Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma) trial, a pivotal phase III randomized controlled study, compared Y-90 radioembolization with oral multi-kinase inhibitor sorafenib monotherapy in patients with advanced HCC^[7]. Although the trial did not demonstrate a statistically significant superiority of Y-90 over sorafenib for overall survival (OS), subgroup analyses suggested potential benefits in select patient populations - particularly those with preserved liver function and limited tumor burden. This trial highlighted the importance of careful patient stratification when considering combination therapies.

The Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients with HCC (SIRveNIB) trial, a phase III randomized trial, also compared OS between patients with advanced HCC managed with Y-90 versus sorafenib^[33]. Again, no significant difference in OS was found, but Y-90 radioembolization demonstrated a superior toxicity profile to sorafenib. These trials underscore the need for additional studies to identify cohorts most likely to benefit from Y-90-based combination strategies.

Several retrospective studies have provided encouraging evidence supporting the additive effects of combining Y-90 with ICIs. Notably, Lee et al. reported results from a 2023 phase I/II trial investigating the efficacy and safety of Y-90 radioembolization combined with durvalumab in patients with unresectable HCC^[8]. This study demonstrated a median progression-free survival (PFS) of 6.9 months and an ORR of 83.3%, outcomes that compare favorably to Y-90 monotherapy (PFS, 3 months; ORR, 42-57%). Importantly, the combination exhibited a tolerable safety profile, with common adverse events including fatigue, hypertension, and transient liver enzyme elevations, all manageable with dose modifications and supportive care^[27].

Another study evaluating the combination of Y-90 with targeted agents demonstrated comparable survival outcomes between groups and confirmed an acceptable safety profile. Facciorusso et al. conducted a retrospective propensity score-matched study of 135 patients with intermediate-to-advanced HCC. Outcomes between Y-90 plus sorafenib and Y-90 alone were compared^[34]. The combination group showed no significant difference in median overall survival (mOS) (10 vs. 10 months; P = 0.711) or PFS (6 vs. 7 months; P = 0.992). Importantly, adverse events were manageable, and no unexpected toxicities were identified^[34].

The rationale for combining Y-90 with targeted therapies centers on disrupting tumor vasculature and cellular proliferation through complementary mechanisms. While Y-90 induces localized radiation damage and vascular disruption, targeted agents inhibit signaling pathways such as VEGFR and PDGFR, mitigating angiogenic rebound and systemic tumor growth. Clinical data to date support the hypothesis that this dual approach may lead to improved local control, delayed disease progression, and potentially enhanced overall survival in carefully selected patients^[7,9,11].

The phase III IMbrave050 trial was designed to evaluate adjuvant atezolizumab plus bevacizumab after curative resection or ablation^[35,36]. An exploratory arm included patients treated with Y-90 before systemic therapy. Preliminary analyses of the Y-90 subgroup showed improved recurrence-free survival compared with historical controls, with no unexpected toxicities.

Phase I and II studies and retrospective series of Y-90 combined with PD-1/PD-L1 blockade (nivolumab, pembrolizumab, atezolizumab) have reported ORRs of 30%-50% and mOS approaching 20 months, exceeding outcomes typically observed with monotherapy. Safety signals were consistent with established ICI profiles, without evidence of enhanced toxicity. For example, the combination of Y-90 and nivolumab in NCT02837029 was tolerable and achieved a clinical benefit rate of 82%, including nine out of eleven patients with stable disease. Key characteristics and outcomes of key clinical trials are summarized in Table 2^[8,37,38,39].

Several prospective studies are in progress. NCT07059494 (phase IV) is evaluating Y-90 with atezolizumab plus bevacizumab in advanced HCC, with PFS and immune correlates as primary endpoints. Additional phase II trials (NCT05809869 and NCT06867432) are assessing Y-90-ICI combinations in advanced and unresectable disease [Table 3]^[40-42].

Transient elevations in liver enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are common following Y-90 treatment due to localized radiation-induced hepatocyte injury and inflammation^[43]. These enzyme elevations are typically self-resolving and peak within weeks of Y-90 treatment. Severe hepatic toxicity, including radiation-induced liver disease (RILD) or liver failure, is rare when patients with preserved hepatic function, generally Child-Pugh class A or early B7, are selected^[43,44]. Therefore, combining Y-90 with systemic therapies, some of which have hepatotoxic potential, necessitates close monitoring of hepatic function to detect early signs of hepatic decompensation and manage accordingly.

Targeted therapies such as sorafenib and lenvatinib present predictable systemic toxicities. Fatigue is among the most common adverse effects reported, alongside hypertension and dermatologic toxicities, including palmar-plantar erythrodysesthesia^[45]. These side effects are typically dose-dependent and manageable through supportive care, dose adjustments, and patient education. Current evidence indicates that the addition of Y-90 radioembolization does not exacerbate these systemic toxicities, supporting the safety of combined regimens with appropriate monitoring^[46].

ICIs can induce immune-related adverse events (irAEs) due to nonspecific immune activation, with manifestations such as immune-mediated hepatitis, colitis, pneumonitis, endocrinopathies, and dermatologic reactions^[47]. While these events can be severe, timely recognition and immunosuppressive treatment are often effective. Data suggest that combining ICIs with Y-90 radioembolization does not significantly increase the frequency or severity of irAEs^[48]. The localized nature of radiation and judicious patient selection may mitigate additive toxicity risks.

Ensuring patient safety requires stringent selection criteria, favoring those with preserved liver function (Child-Pugh A or selected B7) and good performance status (Eastern Cooperative Oncology Group, ECOG 0-1)^[44,45]. Baseline evaluation of liver reserve, portal hypertension, and bilirubin levels informs candidacy and risk stratification. Serial monitoring of liver enzymes, hematologic parameters, blood pressure, and symptoms after treatment facilitates early detection of toxicities and guides timely interventions such as dose modifications or supportive care. This degree of monitoring is facilitated by a multidisciplinary approach.

A pressing priority is the identification and validation of robust molecular and immune biomarkers that predict response or resistance to Y-90 combination therapies. Beyond conventional clinical markers such as AFP, emerging genomic and transcriptomic signatures, immune cell infiltration patterns, and circulating tumor DNA profiles hold promise for refining patient stratification. Such biomarkers could facilitate early identification of responders, guide adaptive treatment modifications, and inform novel agent selection, ultimately enabling a more personalized therapeutic approach.

The evolving landscape of systemic therapies presents opportunities to enhance Y-90 combinations by incorporating next-generation agents. Dual immune checkpoint blockade targeting PD-1/PD-L1 and CTLA-4 pathways, adoptive cell therapies such as chimeric antigen receptor (CAR) T cells or TILs, and agents targeting the fibrotic tumor microenvironment may act synergistically with radiation-induced immunogenic effects. Investigating these combinations could overcome immune evasion mechanisms and potentiate durable antitumor responses, particularly in immunologically “cold” tumors refractory to conventional immunotherapy.

A deeper mechanistic understanding of intrinsic and acquired resistance to both Y-90 and systemic therapies is essential. Tumor heterogeneity, hypoxia-driven angiogenesis, immune suppressive microenvironments, and molecular escape pathways all contribute to treatment failure. Advanced preclinical models and translational studies focusing on tumor-stroma interactions, immune checkpoint dynamics, and angiogenic signaling would enable the design of combination regimens aimed at circumventing resistance.

Future clinical success will hinge on the development and implementation of multidisciplinary care frameworks that integrate expertise across specialties. Streamlined coordination can optimize timing and sequencing, proactively manage adverse effects, and enhance patient adherence and quality of life. Additionally, embedding real-time biomarker monitoring and adaptive trial designs within clinical workflows may accelerate the translation of mechanistic insights into improved therapeutic outcomes.