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Figure 2. Mechanisms of NSCLC immunotherapy resistance. In primary resistance mechanism, KRAS/STK11 co-mutation is the main genomic driver of primary ICI resistance, which reduces lymphocyte infiltration and PD-L1 expression. EGFR is the upstream signaling pathway of KRAS. When EGFR is activated, ILT4 levels rise, which increases the recruitment of M2-TAMs and inhibits immune function. EGFR mutant tumor cells inhibit T cell proliferation and associated functions and exhibit a significant increase in resistance to T cell-mediated killing. In contrast to EGFR WT NSCLC, EGFR mutant tumor cells express a higher level of CD73, and the LAG-3 receptor expressed on T cells is notably upregulated following TKI treatment. At the same time, circ-CPA4 regulates the growth, migration, dryness, and drug resistance of NSCLC cells through the let-7 miRNA/PD-L1 axis. Exhausted MAIT cells produced high levels of IL-17A, which was associated with a poor prognosis. The loss of chromosome 9p21 is associated with primary resistance to ICI and CDKN2A, and MTAP deletions account for about 9.2%. IL-6 can activate the JAK1/STAT3 pathway to enhance PD-L1 expression. The level of IL-6 is negatively correlated with CD8⁺ T cells. VEGF can induce M2 macrophages to enhance the immunosuppressive effect. The overexpression of xCT in TAMs participates in the regulation of the TME, which can promote M2 polarization and inhibit immunity. Mitochondria produce ROS, promote oxidative stress, and immunosuppressive components combine with tumor acidity to maintain tumor growth and block antitumor immune response. In addition, the B2M deletion of HLA-I complex is also associated with immune escape. Figure was created with Biorender.com. NSCLC: Non-small cell lung cancer; KRAS: Kirsten rat sarcoma viral oncogene homolog; STK11: serine/threonine kinase 11; ICI: immune checkpoint inhibitor; PD-L1: programmed cell death-ligand 1; EGFR: epidermal growth factor receptor; ILT4: immunoglobulin-like transcript 4; M2-TAMs: M2 tumor-associated macrophages; WT: wild-type; LAG-3: lymphocyte activation gene-3; TKI: tyrosine kinase inhibitor; MAIT: mucosal-associated invariant T; MTAP: methylthioadenosine phosphorylase; IL-6: interleukin- 6; JAK1: Janus kinase 1; STAT3: signal transducer and activator of transcription 3; VEGF: vascular endothelial growth factor; TME: tumor microenvironment; ROS: reactive oxygen species; HLA-I: human leukocyte antigen-I; M2 Mø: M2 macrophages; P13K: phosphatidylinositol-3-kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin; ICAM1: intercellular cell adhesion molecule-1.