Overcoming Primary and Acquired Resistance to Immunotherapy in Non–Small Cell Lung Cancer: Mechanisms, Challenges, and Emerging Strategies

Acquired resistance (AR) to immune checkpoint inhibitors (ICIs) remains a major obstacle to durable clinical benefit in non–small cell lung cancer (NSCLC). Emerging after initial responses, AR reflects tumor evolution, immune escape, and metabolic reprogramming. Key mechanisms may include impaired antigen presentation (β2-microglobulin, human leukocyte antigen mutations), T-cell exhaustion, and remodeling of the tumor microenvironment (TME). In this review, we summarize the current understanding of ICIs resistance and highlight therapeutic strategies under investigation to overcome it. Novel approaches include next-generation ICIs targeting TIGIT and LAG-3, epigenetic modulators (HDAC, DNMT inhibitors), and metabolic agents relevant to STK11 and KEAP1 mutations. Additional strategies aim to reprogram the TME through AXL or multikinase inhibition, tumor-treating fields, and cytokine- and/or gene-based therapies. Cellular immunotherapies (tumor-infiltrating lymphocytes, T-cell receptors, chimeric antigen receptor-T), antibody-drug conjugates, and vaccines offer complementary means to restore antitumor immunity. Advancing the field will require biomarker-driven patient selection and rational combinations to overcome AR and achieve more durable, personalized immunotherapy outcomes in NSCLC.