Metastasis is a crucial hallmark of malignancy, posing substantial challenges to effective clinical management^[1]. Immunotherapy has demonstrated potential in treating certain metastatic tumors characterized by high mutational burden^[2]. Cancer immunotherapy, particularly immune checkpoint inhibitors, has been approved for clinical use for durable remissions in many metastatic tumors^[3-5]. Distinct from conventional therapeutic modalities, its core advantage is activating the body’s intrinsic immune system for precise tumor elimination, with lower systemic toxicities, durable efficacy, and potential synergistic effects^[6,7]. Despite notable advancements, cancer immunotherapy still confronts unresolved dilemmas, encompassing strategies to augment therapeutic effectiveness across various malignancies and patients, as well as methodologies to forecast patient responsiveness or resistance^[8,9]. Therefore, elucidating the molecular mechanisms underlying clinical outcomes and therapeutic resistance is pivotal to broadening the scope of beneficial impacts derived from immunotherapeutic interventions^[10-12]. Mechanistic insights from the cancer-immunity cycle underscore the potential to enhance immunotherapy efficacy while mitigating acquired immunological tolerance^[13,14]. Effective therapeutic interventions should target resistance mechanisms in malignancies to boost long-term T cell responses and facilitate their iterative expansion^[15,16].

The iterative nature of the antitumor immune response can partially be explained by the cancer-immunity cycle, originally conceptualized in 2013, which refers to a series of stepwise events driving T cell responses to kill tumors in a self-sustaining manner^[17,18]. In brief, the process begins with the release of tumor-associated antigens from dying tumor cells, followed by the processing and presentation of these antigens by antigen-presenting cells, particularly dendritic cells (DCs)^[19-21]. Therapeutic interventions have been employed to promote the release of tumor-associated antigens by inducing tumor death in an immunogenic pathway, involving current clinical scenarios such as chemotherapy^[22], radiotherapy (RT)^[23], and targeted therapy^[24]. In the subsequent steps, vaccines have been recognized as an effective modality to enhance the presentation of antigenic peptides. Meanwhile, blockade of the immune checkpoint cytotoxic Tlymphocyte-associated protein 4 (CTLA4) proves efficient in facilitating T cell priming and activation^[25]. Next, activated effector T cells traffic and infiltrate into tumors and stroma, interact with intratumoral immune cells, and maintain their effector function^[26,27]. Targeting these steps, removal of pathophysiological barriers within the tumor microenvironment (TME) may enhance T cell infiltration, comprising dense extracellular matrix, abnormal angiogenesis, and metabolic derangements^[28,29]. In addition, increasing chemokine levels or inhibiting transforming growth factor also contributes to T cells’ trafficking and infiltration^[30]. Finally, intratumoral effector T cells potentially recognize and eliminate cancer cells, and release additional tumor-associated antigens to favor a self-sustained cycle^[31,32]. Immunotherapeutic approaches such as chimeric antigen receptor T (CAR-T) cell therapy ^[33] and T-cell receptor-engineered T-cell (TCR-T) therapy^[34] are able to yield T cell-mediated cytotoxic responses. Conceivably, programmed cell death ligand-1 (PD-L1) has an inhibitory function that primarily acts to modulate tumor killing^[35,36].

Considering the intricate interplay of numerous factors within the TME, combination therapies are strategically positioned to synergistically complement and sustain the cancer-immunity cycle^[37,38]. Rational integration of multiple treatment modalities, including chemotherapy, phototherapy, gene therapy, and immunotherapy, has been proposed to restore immunosurveillance and reinvigorate pre-existing antitumor immune responses^[39-41]. Engineered nanoplatforms have been designed to act across multiple stages of the cancer-immunity cycle, capitalizing on the pharmaceutical advantages of targeting specificity and stimuli responsiveness^[42-44]. The rapid advancement of nanomaterials offers unprecedented opportunities for precise immune modulation with tolerable immune-related adverse events^[45,46].

To date, a variety of nanoplatforms have entered clinical trials, involving lipid nanoparticles (LNPs)^[47,48], polymeric nanoparticles^[49], inorganic nanomaterials^[50], and exosome-mimetic nanovesicles^[51]. For example, LNPs, notable for their adjustable size, easy surface modification, and biocompatibility, have emerged as pivotal tools in facilitating the controlled release of immunostimulatory agents (BNT122, NCT03289963) and potent vaccination (mRNA-4157, NCT03897886)^[52-54]. The polymeric nanoformulation of AZD4635 is currently undergoing Phase II trials (NCT04089553), demonstrating outstanding biosafety and precise drug release capabilities in cancer immunotherapy^[55]. Research into metalloimmunotherapy involves inorganic nanomaterials such as MnO₂, and gold nanoparticles have been approved for image-guided radioimmunotherapy^[56,57]. Mesenchymal stromal cell-derived iExosomes (NCT03608631) or DC-derived exosome (NCT01159288) exhibit unique advantages in tumor targeting and immune modulation in clinical settings^[58-60]. Although certain nanomedicines have gained approval for clinical trials, the issue of metastases caused by hematogenous dissemination of circulating tumor cells remains a tough clinical issue^[61]. Smart nanomaterials possess natural immune-stimulating properties or incorporate immunomodulatory adjuvants, and have precipitated a transformative breakthrough in overcoming delivery barriers and optimizing therapeutic efficacy^[62,63].

By integrating diverse therapeutic modalities, nanomaterials effectively address critical challenges in cancer immunotherapy, particularly in microenvironment remodeling, therapeutic optimization, and the suppression of tumor metastasis. This review elucidates the synergistic potential of nanomaterials in reinitiating the cancer-immunity cycle when combined with chemotherapy, RT, phototherapy, sonodynamic therapy, metabolic regulation, and neuro-immune interactions, with a specific focus on strategies to target and eliminate disseminated tumor cells at metastatic sites [Figure 1]. Furthermore, the rational design of functionalized nanoplatforms, encompassing material selection, structural configuration, and the application of artificial intelligence (AI), is discussed in terms of overcoming physiological barriers, counteracting the immunosuppressive microenvironment, and preventing metastatic colonization. Current challenges and future opportunities in engineering nanomaterials to synergistically modulate the immunosuppressive microenvironment and restore antitumor immunity are also discussed. This review highlights nanomaterial-supported combined immunotherapy methods, offering crucial insights for optimizing treatment outcomes, inhibiting distant metastasis, and moving towards clinical translation.

Clinical evidence has shown the shortcomings of monotherapies in handling metastatic tumors, prompting the swift advancement of combined treatment approaches recently. Clinically validated combinations have demonstrated notable potential in different solid tumors, improving progression-free survival (PFS) and objective response rate (ORR) [Table 1]. Typically, combining immune checkpoint inhibitors with chemotherapy has become a standard of care for non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), and head and neck squamous cell carcinoma (HNSCC).

For patients with unresectable hepatocellular carcinoma (HCC), transarterial chemoembolization (TACE) appears to be superior first-line therapy, while the conversion rate from this locoregional therapy is only about 10%. Promising results from the complex triple combination of lenvatinib, TACE, and PD-1 inhibitors (LEN-TAP) regimen, have led to a higher rate of salvage liver resection (SLR) than TACE alone, at 59.2% compared to 18.3%^[64]. In another phase II trial in metastatic breast cancer, combinational treatment of metronomic chemotherapy plus anti-PD-1 (αPD-1) significantly prolonged the patient’s PFS^[65]. This regimen demonstrates favorable safety and systemic immune reprogramming in refractory malignancies, representing a promising option for patients with aggressive, typically immunologically cold breast cancer.

Radio-immunotherapy has demonstrated its efficacy in patients with a low tumor mutation burden, and may expand the therapeutic window of checkpoint blockade for low response rates^[66,67]. In cases of metastatic NSCLC, the combination of stereotactic body radiation therapy (SBRT) followed by pembrolizumab (NCT02492568) resulted in a longer PFS compared to SBRT alone (15.56 vs. 4.39 months)^[68]. This approach exhibits superior efficacy in immunologically cold tumors characterized by low tumor mutation burden, PD-L1 negativity, and Wnt mutations. In a landmark study, minimally invasive cryoablation may also affect host immune responses and sensitivity to therapeutic interventions^[69]. When combined with checkpoint inhibitor sintilimab and lenvatinib, partial cryoablation in advanced or metastatic intrahepatic cholangiocarcinoma significantly increased the ORR^[70]. However, it also faces several major limitations, including a small single-arm population, lack of independent central review, and unvalidated efficacy in patients with the combined treatment regimen of gemcitabine, cisplatin, and immune checkpoint inhibitors (GemCis-ICI) refractory disease.

The gut microbiota is increasingly recognized as a pivotal factor in cancer pathogenesis and treatment response. Fecal microbiota transplantation (FMT) has emerged as a promising strategy to modulate the microbiome and reshape the immune landscape^[71]. Results from the Phase 2 TACITO trial demonstrated that FMT combined with immune checkpoint inhibitors for the treatment of metastatic renal cell carcinoma was associated with a significant increase in PFS (24.0 months vs. 9.0 months) and ORR (52% vs. 32%) compared with patients receiving placebo therapy^[72]. Additionally, microbiome profiling confirmed the engraftment of donor strains, along with increased α-diversity and more pronounced shifts in microbiome composition of β-diversity relative to baseline in the FMT-treated group. This combination therapy offers durable clinical benefits and effective microbiome reprogramming via successful donor engraftment, yet is constrained by small sample size, insufficient baseline balance, reliance on a single donor, and challenges in stable stool supply.

Given the elevated expression of mesothelin, nanobody-functionalized CAR-T cells targeting mesothelin and equipped with αPD-1 nanobodies (referred to as NAC-T) have been strategically constructed^[73]. Recently, a first-in-human clinical trial was performed in 11 patients with refractory malignant mesothelioma who had failed standard therapies. The NAC-T treatment demonstrated favorable safety, with an overall response rate of 63.6%, and the disease control rate reached 100%. The median PFS was 5.0 months, and the median overall survival was prolonged to 25.6 months. These clinical results underscore the promising translational potential of combinational nanobody-mediated immune checkpoint inhibition with CAR-T therapy.

Despite advances in clinical management, effectively inhibiting distant tumor metastasis remains one of the most formidable challenges in contemporary oncology^[74,75]. The primary obstacles for combinatorial antimetastatic regimens are major off-target effects^[76]. Non-specific biodistribution and off-target drug release may initiate excessive inflammation and lead to immune-related adverse events^[77]. By using specific ligands for surface modification, engineered nanoparticulate formulations actively target metastatic tumors, leading to increased accumulation at the tumor site and reduced unintended exposure to healthy tissues^[78]. Nanocarriers that respond to the TME allow for controlled drug release triggered by pathological characteristics, thereby minimizing early leakage and off-target effects^[79,80]. Emerging nanomaterials for cargo delivery have demonstrated compelling potential in improving therapeutic selectivity and reducing immune-related adverse events^[81,82].

The metastatic process typically encompasses several stages, beginning with the intravasation of primary tumor cells into the vasculature, followed by hematogenous dissemination, extravasation into distant organ sites, and culminating in the colonization and proliferation of secondary lesions [Figure 2]. Malignant progression often results in the development of secondary lesions in distant organs such as the lungs, liver, bones, and brain, significantly compromising patient outcomes and diminishing long-term survival.

Nanomaterial-enabled combinational immunotherapies can effectively enhance the delivery of immunomodulatory agents, target immune cells, modulate the TME, and overcome tumor immune evasion. Specifically, nanoplatforms have shown remarkable efficacy in amplifying DNA damage, inducing ICD, activating the STING pathway, and synergizing with various immunotherapeutic modalities to suppress tumor growth and metastasis. Additionally, the integration of nanotechnology with AI has provided a novel paradigm for personalized therapeutic design, optimizing drug delivery and dosage to further improve treatment outcomes. However, current challenges still hinder the practical translation of these nanomaterial-driven immunotherapies into clinical applications.

Despite significant advancements in the field of smart nanomaterial-driven combinatorial immunotherapy, several critical challenges continue to impede its clinical translation. Firstly, the scalable synthesis of these materials with consistent batch-to-batch reproducibility remains a significant bottleneck, as standardized manufacturing protocols and quality control systems for combinatorial regimens are still underdeveloped. Moreover, the heterogeneous nature of the TME results in variable therapeutic responses, with inadequate tumor selectivity leading to off-target effects. Issues such as nonspecific accumulation of nanocarriers in healthy tissues, uncontrolled co-release of therapeutic payloads, and aberrant immune activation collectively undermine the safety and efficacy of treatments. Besides, therapeutic resistance induced by the TME and the complex interplay between distinct immunotherapeutic modalities present additional obstacles to achieving effective treatment outcomes. Furthermore, the complexities of combination therapies, such as optimizing the ratio of nanomaterials to immunomodulatory agents, coordinating the timing of different therapeutic modalities, and addressing potential drug-drug interactions, add layers of difficulty to clinical implementation. Absence of unified regulatory standards and clinical evaluation protocols specifically designed for nanomaterial-based combined immunotherapies further delays their clinical approval and commercialization. A comprehensive understanding of metastatic biology, key signaling pathways, and emerging therapeutic strategies is thus critical to improving the diagnosis and treatment of metastatic malignancies.

Future directions should focus on addressing these existing challenges to bridge the gap between laboratory successes and clinical applications. Refining nanoplatform engineering with AI will be crucial for improving targeting precision, minimizing adverse effects, and optimizing therapeutic efficacy, as AI-driven design can predict nanomaterial behavior and tailor formulations to individual patients. Establishing standardized manufacturing protocols and quality control systems to ensure reproducibility of combined immunotherapies is necessary to optimize scalable synthesis and ensure consistency. Conducting large-scale animal studies is essential to establish the long-term safety and efficacy of nanomaterial-enabled immunotherapies, strengthening interdisciplinary collaboration between nanotechnology and immunology to optimize synergistic interactions, thereby advancing the clinical translation of combinatorial immunotherapies and improving patient outcomes.