Antibody–Drug Conjugates in Lung Cancer: Promise, Progress, and Persistent Challenges

Lung cancer is currently the most frequently diagnosed malignancy worldwide, ac-counting for approximately 12.4% of all cancers and, despite major advances in molec-ularly targeted therapies and immunotherapy, represents the leading cause of can-cer-related mortality, In recent years, antibody–drug conjugates (ADCs) have emerged as a novel therapeutic strategy, combining the specificity of monoclonal antibodies with the potent cytotoxic activity of highly active payloads to selectively target tumor cells while limiting systemic toxicity. This review summarizes the current role of ADCs in lung cancer, with particular focus on their structural components, mechanisms of action, and the biological features that determine treatment efficacy. We discuss the rationale for tar-geting established and emerging antigens in non-small cell and small cell lung cancer, including HER2, TROP2, c-MET, HER3, CEACAM5, DLL3, and other promising targets currently under clinical investigation. The principal mechanisms of primary and acquired resistance are also reviewed, including antigen modulation, altered intracellular trafficking, lysosomal dysfunction, drug efflux, tumor microenvironment-mediated immune suppression, and intratumor heterogeneity. In addition, we provide an over-view of the safety profile of ADCs, highlighting the most clinically relevant adverse events and their underlying biological mechanisms. We also examine the evolving landscape of predictive biomarkers beyond antigen expression, including genomic, transcriptomic, proteomic, and liquid biopsy-based approaches, together with emerging spatial and single-cell technologies that may improve patient selection. Finally, we discuss future directions in the field, including novel payloads, next-generation linker technologies, bispecific ADCs, combination strategies, and personalized ADC devel-opment. Overall, ADCs are rapidly reshaping the therapeutic landscape of lung cancer. Continued optimization of drug design, biomarker-driven patient selection, and a deeper understanding of resistance mechanisms will be essential to fully realize their clinical potential.