Antibody-Drug Conjugates in Solid Tumors: Mechanisms, Clinical Advances, and Emerging Resistance Patterns

Introduction: Antibody-drug conjugates (ADCs) represent a transformative therapeutic modality in oncology, combining targeted antibody delivery with potent cytotoxic payloads. This narrative literature review examines ADC development for solid tumors, emphasizing advances from 2022-2025 while incorporating foundational trials from 2017-2021. Methods: We conducted comprehensive searches of PubMed, Embase, and major oncology conference proceedings (ASCO, ESMO, AACR) from January 2020 through December 2025, with emphasis on literature published since 2022. Search terms included: antibody-drug conjugates, ADC, solid tumors, specific agent names (trastuzumab deruxtecan, sacituzumab govitecan, enfortumab vedotin, tisotumab vedotin, datopotamab deruxtecan), resistance mechanisms, and combination therapy. We prioritized phase 2 and 3 clinical trials, mechanistic studies, and high-quality systematic reviews, clearly distinguishing phase 2 response data from comparative survival outcomes. Results: Topoisomerase inhibitor-based ADCs demonstrated substantial activity across multiple tumor types. In HER2-positive breast cancer, trastuzumab deruxtecan achieved superior outcomes compared to trastuzumab emtansine in DESTINY-Breast03. HER2-targeted ADCs achieve higher response rates than tissue antigen-targeted ADCs, though comparisons are limited by population heterogeneity. Multiple resistance mechanisms include antigen downregulation, impaired internalization, and payload efflux. Established targets (HER2, TROP2, Nectin-4) have FDA-approved ADCs, while emerging targets (B7H3, CEACAM5) are under investigation. Combination strategies with immunotherapy show promising synergy. Conclusions: ADCs have established clinical utility across solid tumors, with ongoing innovation in linker technology, payload selection, and target identification. Next-generation ADCs incorporating bispecific antibodies and dual payloads represent promising directions. Definitive evidence of improved long-term outcomes is needed before widespread adoption in curative-intent settings.