Overcoming immunotherapy resistance in non-small cell lung cancer: a narrative review of related factors

Non-small cell lung cancer (NSCLC) accounts for over 80% of lung cancer cases and is often diagnosed at advanced stages. Resistance to immunotherapy in NSCLC involves genetic mutations, tumor microenvironment (TME) characteristics, treatment history, and age-related factors. Despite increasing use of immune checkpoint inhibitors (ICIs), resistance mechanisms remain poorly understood. Key genetic alterations associated with resistance include STK11, KEAP1, and EGFR mutations, particularly with low tumor mutational burden (TMB). The immunosuppressive tumor microenvironment, characterized by regulatory T cells and myeloid-derived suppressor cells, can hinder ICI efficacy. Metabolic alterations and deficient antigen presentation contribute to resistance. Prior treatments can alter the tumor microenvironment, affecting subsequent immunotherapy responses. Age-related factors, including immunosenescence, influence resistance, with older patients having higher TMB and more immunogenic microenvironments. Strategies to overcome resistance include combination therapies, biomarker-driven approaches, and targeting novel pathways. Combining ICIs with chemotherapy or radiation can enhance antitumor responses. Biomarker approaches, such as TMB and PD-L1 expression assessment, help tailor therapies. Exploring novel targets like RIG-I and STING pathways may provide additional solutions. Understanding these factors is crucial for developing personalized strategies to overcome immunotherapy resistance in NSCLC.