Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-associated mortality worldwide. Immune checkpoint inhibitors targeting programmed cell death protein 1, programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 have transformed the treatment landscape of NSCLC. However, primary and acquired resistance limit durable clinical benefit. The current review article aimed to summarize tumor microenvironment-mediated resistance as an interconnected biological process rather than a collection of isolated factors. Immunosuppressive myeloid populations, regulatory lymphocytes, cancer-associated fibroblasts, extracellular matrix remodeling, vascular endothelial growth factor-driven vascular dysfunction, hypoxia, transforming growth factor-β signaling and metabolic reprogramming cooperate with defects in antigen presentation, dysregulation of serine/threonine kinase 11/Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2/stimulator of interferon genes and oncogenic driver signaling to generate immune-desert (minimal immune cell infiltration), immune-excluded (immune cells retained outside tumors) or exhausted immune-inflamed (immune-cell infiltration with functional exhaustion) phenotypes. The present review also critically evaluated combination therapeutic strategies, distinguishing phase III-supported standards from early-phase clinical or preclinical approaches, while highlighting considerations associated with patient selection, toxicity and the evolving regulatory context. Finally, an operational biomarker framework integrating PD-L1 expression, tumor mutational burden, interferon γ-associated signatures, spatial profiling, circulating tumor DNA, exosomal biomarkers and microbiome features was proposed to guide precision immunotherapy in NSCLC.
