PROGRESS AND MECHANISMS OF ANTIBODY-DRUG CONJUGATES IN NSCLC THERAPY

Antibody–drug conjugates (ADCs) are emerging as a transformative therapeutic modality for non-small cell lung cancer (NSCLC), bridging the tumor selectivity of monoclonal antibodies with the potent cytotoxicity of chemotherapy payloads. This review summarizes recent clinical progress of ADCs in NSCLC and highlights key design features that shape efficacy and safety, including antigen selection, linker chemistry, payload class, drug–antibody ratio, and the bystander effect. Particular emphasis is placed on clinically advanced targets—HER2, TROP2, HER3, and MET—as well as promising emerging antigens such as B7-H3. Across multiple studies, next-generation ADCs have shown meaningful activity in molecularly defined and treatment-refractory populations, including patients with acquired resistance to EGFR-targeted therapy and those harboring HER2 alterations. However, ADC use is constrained by distinctive toxicities, notably interstitial lung disease/pneumonitis associated with certain topoisomerase I inhibitor payloads, alongside myelosuppression and gastrointestinal adverse events. We further discuss evolving resistance mechanisms (antigen downregulation, impaired internalization, efflux transporters, and microenvironmental barriers) and outline future directions, including biomarker-guided patient selection, rational sequencing, and combination strategies with immune checkpoint inhibitors or targeted agents. Collectively, ADCs are poised to become an integral component of precision therapy for NSCLC, contingent on optimized design and proactive toxicity management.