Comparative Mechanistic Fitness and Clinical Translation of CAR-T Cells, Immune Checkpoint Inhibitors, and Antibody–Drug Conjugates in NSCLC

University of Leeds; Woodhouse Lane, Leeds West Yorkshire LS2 9JT ; United Kingdom

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Abstract

Immunotherapy has become a cornerstone of treatment for non-small cell lung cancer (NSCLC). This review summarizes the major immunotherapy strategies: immune checkpoint inhibitors (ICIs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T cell (CAR-T) therapy and analyzes how their mechanisms align with distinct tumor immune phenotypes. Specifically, ICIs, through PD-1/PD-L1 blockade, restore antitumor immunity in "hot" tumors and produce durable survival benefits across multiple stages of NSCLC. In contrast, ADCs deliver cytotoxic payloads via target-specific antibodies, thereby offering immune-independent efficacy in "cold" or ICI-refractory tumors. However, toxicities such as interstitial lung disease may be dose-limiting. Transitioning to CAR-T therapy, although this approach is highly effective in hematologic malignancies, it remains experimental in NSCLC due to antigenic heterogeneity, poor T cell infiltration, and a suppressive tumor microenvironment. Notably, early studies, including intrapleural administration of mesothelin-targeted CAR-T cells combined with PD-1 blockade, have demonstrated local activity and safety. By combining mechanistic insights from ICIs and ADCs with next-generation CAR-T engineering, future development of more adaptable immunotherapies for solid tumors may be guided. Keywords: Non-small cell lung cancer (NSCLC); immune checkpoint inhibitors (ICIs); antibody-drug conjugates (ADCs); CAR-T cell therapy; tumor microenvironment; antigen heterogeneity; immunotherapy resistance.