The management of locally advanced or metastatic solid tumors remains a formidable challenge in clinical oncology (1). While conventional chemotherapy continues to be a cornerstone, the advent of targeted therapies and immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized treatment paradigms. ICIs, by reactivating the host immune system against cancer cells, have demonstrated remarkable and durable responses across a spectrum of malignancies (2–4). However, the benefits of immunotherapy are not universal; a significant proportion of patients exhibit primary resistance, and many who initially respond eventually develop acquired resistance (5, 6). This stark reality underscores the critical need for novel combination strategies designed to amplify anti-tumor immunity and overcome the limitations of monotherapy.

Disitamab vedotin (DV) is an innovative antibody-drug conjugate (ADC) that targets the Human Epidermal Growth Factor Receptor 2 (HER2) (7, 8). Its unique design incorporates a hertuzumab-derived antibody with a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE) (8, 9). A key advantage of DV is its ability to exert cytotoxic effects not only in tumors with high HER2 expression but also in those with lower HER2 expression levels, a population often ineligible for traditional HER2-targeted treatments (10, 11). Beyond its direct cytotoxic payload delivery, emerging preclinical evidence suggests that DV can induce immunogenic cell death, a process that may enhance tumor immunogenicity by promoting antigen presentation and fostering a favorable tumor microenvironment (12, 13). This mechanism provides a strong scientific rationale for combining DV with ICIs, with the potential to synergistically boost T-cell-mediated anti-tumor activity and reverse immunotherapy resistance.

Consequently, several clinical trials have begun to explore the combination of DV and ICIs, reporting promising preliminary activity in various solid tumors, such as urothelial carcinoma and gastric cancer (14, 15). However, the current evidence is fragmented across early-phase studies with limited sample sizes. The overall efficacy, safety profile, and consistency of this combination regimen have not been comprehensively evaluated. Therefore, we will conduct this systematic review and meta-analysis to synthesize all available clinical evidence about the efficacy and safety of DV plus immunotherapy, thereby offering crucial insights for clinical decision-making and the design of future definitive trials.

The protocol for this systematic review was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD420251154446). The conduct and reporting of this study adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (16). A completed PRISMA checklist is provided in Supplementary Table 1 to ensure comprehensive and transparent reporting.

This systematic review and meta-analysis represent the first study to evaluated the efficacy and safety of DV in combination with immunotherapy in patients with locally advanced or metastatic solid tumors. Pooled results from 21 studies involving 1183 patients demonstrated an encouraging ORR of 53%, a DCR of 82%, and a mPFS of 7.8 months. The safety profile was manageable, with hematological and neurological events representing the most common treatment-related adverse events. These findings suggest that the combination of DV and ICIs offers a promising therapeutic strategy for this patient population.

Compared to traditional chemotherapy, which typically yields ORRs of 30–50% in advanced solid tumors but is often associated with considerable toxicity (33, 39–41), the DV-ICI regimen not only achieves higher response rates but also exhibits a distinct and manageable safety profile. This superiority is further corroborated by the recent phase III RC48-C016 trial, which directly compared DV plus Toripalimab with platinum-based chemotherapy in previously untreated HER2-expressing locally advanced or metastatic urothelial carcinoma (33). The trial demonstrated a significant improvement in both PFS (median 13.1 vs. 6.5 months; HR 0.36) and overall survival (median 31.5 vs. 16.9 months; HR 0.54) with the combination therapy, establishing a new benchmark for first-line treatment in this setting. In addition, our subgroup analysis observed superior efficacy in the first-line setting (ORR: 71%) compared to later lines (ORR: 52%). Therefore, these results support the consideration of this regimen as a first-line option, particularly in HER2-expressing tumors.

The integration of DV into the therapeutic landscape for certain solid tumors has spurred growing interest in exploring its combination with other treatment modalities to improve clinical outcomes (42–46). Compared with historical results from DV monotherapy in HER2-expressing solid tumors, combining DV with immunotherapy demonstrates significantly enhanced antitumor activity. The synergistic efficacy observed with DV and ICIs is underpinned by multifaceted complementary mechanisms that converge to remodel the tumor immune microenvironment. As a HER2-targeted ADC, DV not only delivers MMAE directly to HER2-expressing tumor cells, inducing caspase-dependent apoptosis and immunogenic cell death, but also elicits broader immunomodulatory effects (13). The ICD triggered by DV involves the release of damage-associated molecular patterns, such as ATP and calreticulin, which act as potent danger signals to recruit and activate dendritic cells. This promotes phagocytosis of tumor antigens and cross-presentation to CD8+ T cells via major histocompatibility complex class I molecules, thereby priming a de novo antitumor T-cell response (47). Concurrently, DV’s bystander effect—enabled by the permeable payload MMAE—can eradicate adjacent HER2-low or heterogeneous tumor cells, further amplifying antigen spread and reducing immune escape. In addition, ICIs augment this response by blocking inhibitory checkpoints (e.g., PD-1/PD-L1), which reverses T-cell exhaustion and prevents the engagement of co-inhibitory receptors on activated T cells (48). This dual approach transforms immunologically “cold” tumors into “hot” ones: DV-induced ICD provides the necessary antigenic stimulus and co-stimulatory signals, while ICIs sustain T-cell effector functions by mitigating adaptive resistance. Preclinical models reinforce this synergy; for instance, in HER2-positive murine tumors, DV monotherapy increased tumor-infiltrating lymphocytes and upregulated PD-L1 expression on both tumor and immune cells—a adaptive feedback mechanism that paradoxically enhances susceptibility to anti-PD-1 therapy (49, 50). Furthermore, DV has been shown to activate the cGAS-STING pathway, fostering type I interferon production and natural killer cell recruitment, which synergizes with ICI-mediated T-cell cytotoxicity (51). Despite these compelling mechanisms, robust clinical validation through randomized trials is imperative to confirm the translational relevance of these pathways and optimize combination strategies.

In the safety analysis of this study, it was observed that TRAEs associated with DV combined with ICIs were primarily attributable to DV. Furthermore, during the literature screening process, we noted that in some studies, the incidence of grade ≥3 TRAEs with the combination therapy appeared higher than that reported with DV monotherapy. Although the present analysis did not directly compare TRAE rates between DV-ICI combination and DV monotherapy, the above findings suggest that ICIs may potentially increase the incidence of grade ≥3 TRAEs associated with DV. Possible explanations for this observation include immune system activation by ICIs, which might exacerbate inflammatory responses or alter the tissue tolerance threshold, thereby intensifying the toxic effects of the cytotoxic payload released by DV (48). Additionally, immune-mediated tissue damage may impair the repair mechanisms typically invoked by DV-induced injury, leading to higher-grade adverse events. However, a previous meta-analysis focusing on ADCs combined with immunotherapy in solid tumors demonstrated comparable incidences of grade ≥3 TRAEs between combination therapy and ADC monotherapy (40). It should be noted, however, that this earlier study did not include DV. Therefore, further well-designed studies are warranted to clarify the safety profile of DV in combination with ICIs compared to DV alone (52).

Subgroup analysis revealed that HER2-positive tumors exhibited a significantly higher ORR (67%) compared to HER2-negative cases (50%). This aligns with the known mechanism of action of DV as an HER2-directed antibody-drug conjugate, supporting the dependence on target antigen expression for optimal drug internalization and payload delivery (53). However, the clinically meaningful response observed even in HER2-low populations underscores the potential of DV to address a broader patient group beyond conventional HER2-positive classifications, possibly due to the bystander effect of the membrane-permeable MMAE toxin. Furthermore, the heterogeneity of HER2 expression should also be taken into consideration, as we previously observed in upper tract urothelial carcinoma (54).

The findings from this meta-analysis indicate that the combination of DV and ICIs could represent a new standard of care for certain advanced solid tumors, especially in urothelial carcinoma and HER2-positive gastric cancer. This strategy leverages both targeted cytotoxicity and immunoactivation, potentially transforming outcomes in populations with limited treatment options. Moreover, the tolerable safety profile facilitates clinical applicability and combination feasibility.

Several limitations should be acknowledged. First, the included studies were predominantly retrospective and single-arm, introducing potential selection bias and unmeasured confounding. Second, significant heterogeneity was observed across studies, possibly due to variations in tumor types, HER2 assessment methods, and treatment protocols. Third, the limited number of studies in certain subgroups (e.g., gastric cancer) constrained deeper comparative analyses, and longer-term outcomes such as overall survival could not be robustly evaluated due to insufficient data maturation and inconsistent reporting. Furthermore, the generalizability of our findings may be constrained by the predominance of studies conducted in Chinese populations. Potential influences of genetic background, regional therapeutic practices, and socio-demographic factors on treatment efficacy and safety warrant consideration. Thus, the extrapolation of these results to other ethnic groups requires validation through future multi-regional studies.

This study provides a comprehensive synthesis of the current evidence on DV combined with immunotherapy for locally advanced or metastatic solid tumors. The results confirm that this combination regimen yields meaningful clinical efficacy, as evidenced by substantial ORR, DCR, and mPFS, alongside a predictable safety profile primarily characterized by DV-associated toxicities. The enhanced efficacy observed in HER2-positive tumors and in the first-line setting offers valuable guidance for patient selection and clinical trial design. Despite the limitations inherent in the included retrospective studies, the findings strongly suggest that the DV-ICI combination is a viable and promising treatment strategy. Future prospective, randomized trials are warranted to definitively establish its efficacy and safety relative to standard of care, and to further explore predictive biomarkers for response.