Antibody–drug conjugates in gastric cancer: from targeted cytotoxicity to immune modulation

Abstract

Gastric cancer (GC) remains a major cause of cancer-related mortality, and therapeutic resistance and tumor heterogeneity continue to limit durable responses in advanced disease. Antibody–drug conjugates (ADCs), which combine the target specificity of monoclonal antibodies with highly potent cytotoxic payloads, have emerged as an important component of biomarker-guided therapy. Beyond selective payload delivery, accumulating evidence indicates that ADCs can interact with antitumor immunity through Fc-mediated immune-effector functions, immunogenic tumor-cell death, enhanced antigen presentation, recruitment of effector T cells, and remodeling of the tumor immune microenvironment. In this review, we summarize the structural and pharmacological principles of ADCs and discuss established and emerging targets in GC, including HER2, CLDN18.2, HER3, GCC, TROP2, Nectin-4, EGFR, and MUC1. Particular emphasis is placed on the immunological consequences of ADC treatment and the mechanistic rationale for combining ADCs with immune checkpoint inhibitors. We further discuss tumor heterogeneity, resistance mechanisms, biomarker selection, treatment-related toxicities, and emerging combination strategies. Integrating tumor-antigen biology with immune-contextual features may enable more rational patient selection and therapeutic combinations. Collectively, next-generation ADCs may function not only as targeted cytotoxic agents but also as modulators of antitumor immunity in gastric cancer.