Precision Warfare in Solid Tumors: Molecular Mechanisms and Emerging Frontiers of Antibody-Drug Conjugates.

Abstract

Background: Antibody-drug conjugates (ADCs) have transformed the treatment of solid tumors by combining the tumor specificity of monoclonal antibodies with highly potent cytotoxic payloads. Advances in ADC engineering have expanded their clinical applications while addressing limitations of conventional chemotherapy and targeted therapies.Methods: We conducted a comprehensive narrative review of the molecular mechanisms, structural design, resistance pathways, clinical translation, and emerging engineering strategies of ADCs in solid tumors, integrating evidence from preclinical and clinical studies.Results: ADC efficacy is governed by antigen selection, linker chemistry, payload characteristics, and drug-to-antibody ratio, which collectively influence pharmacokinetics, tumor penetration, intracellular trafficking, and payload release. Key mechanisms include receptor-mediated internalization, lysosomal processing, bystander killing, immune modulation, and interactions with the tumor microenvironment. Major resistance mechanisms comprise antigen heterogeneity, impaired intracellular trafficking, drug efflux, adaptive DNA repair, and stromal barriers. Emerging innovations-including site-specific conjugation, bispecific and conditionally activated ADCs, novel payloads, biomarker-guided patient selection, and rational combination therapies-are enhancing therapeutic efficacy and expanding targetable tumors.Conclusion: Continued advances in molecular engineering and precision biomarker strategies are redefining ADCs as versatile platforms for precision oncology and may enable broader, potentially tumor-agnostic, applications in solid tumors.