Clinical applications of antibody-drug conjugates in advanced non-small cell lung cancer

Lung cancer remains the leading cause of cancer-related incidence and mortality worldwide, with non-small cell lung cancer (NSCLC) constituting the majority of cases. Current treatment modalities are constrained by significant limitations: conventional chemotherapy exhibits poor tumor selectivity and systemic toxicity, while monoclonal antibodies frequently demonstrate inadequate therapeutic efficacy. Antibody-drug conjugates (ADCs)-engineered biotherapeutics comprising tumor-targeting antibodies conjugated to potent cytotoxic agents through optimized linkers-have emerged as a transformative strategy to address these therapeutic challenges in advanced NSCLC. This review systematically examines the structural architecture, developmental evolution, and mechanistic foundations of ADCs, with a focused evaluation of clinical evidence supporting ADCs targeting HER2, TROP2, c-MET, HER3, CEACAM5, and B7-H3 in advanced NSCLC. We critically assess efficacy outcomes, safety profiles, predictive biomarkers, and toxicity management strategies-particularly regarding interstitial lung disease, hematologic toxicities, and neuropathic adverse events. Key clinical challenges including tumor heterogeneity, therapeutic resistance, biomarker heterogeneity, and patient stratification are analyzed. Furthermore, we highlight emerging therapeutic approaches such as next-generation ADC design, novel linker-payload systems, bispecific platforms, and rational combination strategies with targeted and immunotherapeutic agents. Collectively, these developments position ADCs as promising precision oncology tools capable of reshaping treatment paradigms and improving clinical outcomes in advanced NSCLC.