Antibody–drug conjugates combined with immune checkpoint inhibitors in cancer: mechanisms, clinical evidence, and translational challenges

Immune checkpoint inhibitors (ICIs) have become an important component of cancer therapy, but primary resistance, acquired resistance, cold or immune-excluded tumor states, and immune-related adverse events continue to limit durable benefit. Antibody-drug conjugates (ADCs), while designed for targeted delivery of cytotoxic payloads, may also influence tumor cell death, antigen release, and local immune responses, providing a drug-design rationale for combination strategies with immunotherapy. Mechanistically, intratumoral ADC exposure and immune effects are shaped by the antibody, linker, payload, target internalization, and bystander effect, with implications for immunogenic cell death (ICD), the release of damage-associated molecular patterns (DAMPs), activation of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling and Toll-like receptor (TLR) signaling, and remodeling of the tumor immune microenvironment (TIME). Clinical studies now span urothelial cancer, breast cancer, gynecologic malignancies, hematologic malignancies, lung cancer, and gastrointestinal cancers; interpretation of these findings requires attention to cancer type, target expression, payload class, treatment line, prior ICI exposure, and study design. Target heterogeneity, peripheral immune status, organ function, and comorbidities may further affect efficacy interpretation, toxicity attribution, and subsequent treatment selection. Further clinical translation should integrate biomarker development and patient stratification with resistance mechanisms, sequential therapy, quality of life, and treatment affordability, so that regimen design, patient selection, and safety management can be evaluated more clearly in prospective studies.