Engineering the Future of ADCs in Non-Small Cell Lung Cancer

Antibody–drug conjugates (ADCs) are a promising strategy in non-small cell lung cancer (NSCLC), but early-generation drugs were limited by suboptimal target selection, heterogeneous drug–antibody ratios, and linker instability, resulting in modest efficacy and relevant toxicities. We performed a narrative review based on a literature search of PubMed and major oncology congresses up to October 2025, with the aim to critically analyzing the evolving biomarker landscape and engineering strategies shaping next-generation ADC development in NSCLC. Emerging approaches to identify targets for ADCs and refine patient selection include digital pathology with artificial intelligence technologies, transcriptomic and proteomic profiling, and liquid biopsy. Modern platforms incorporate site-specific conjugation technologies to achieve controlled and homogeneous drug-to-antibody ratio (DAR) distributions, improving pharmacokinetic predictability and reducing off-target effects. Advances in linker chemistry enhance plasma stability while preserving efficient intracellular payload release, balancing bystander effect with safety. These innovations are designed to enhance tumor selectivity, mitigate off-target toxicity and overcome resistance mechanisms. In conclusion, next-generation ADCs in NSCLC integrate refined biomarker strategies with advances in antibody engineering, linker design and payload biology. Emerging approaches, including immune-stimulating and bispecific ADCs, novel payloads, and combinations with tyrosine kinase inhibitors (TKIs) or immunotherapy, may improve efficacy, overcome resistance and expand the therapeutic window. Bispecific and dual-payload ADCs, as well as immune-stimulating ADCs, further aim to overcome resistance, exploiting both direct cytotoxicity and immune system activation and positioning ADCs as a crucial component of precision oncology in NSCLC.