Table 2.

Summary of mechanism of immunotherapeutic resistance and prospective targets in lung cancer.

Resistance Mode	Action	Target	References
Gene mutations	a. Modify the expression of PD-1, PD-L1, and CTLA-4 proteins b. Deregulate PD-1/PD-L1 signaling pathways	ALK, EGFR, HER-2, CDK2NA, STK11 (LKB1); TP53; KRAS	[219,221,226,227]
Dysregulation of cellular and molecular pathways	a. Promote primary and adaptive resistance to anti-CTLA-4 and anti-PD-1 b. Enhance cancer cell proliferation and metastasis	Wnt/B-catenin, JAK/STAT3, PI3K-Akt, JAK1/2 mutations, IFN-γ signaling pathways	[215,222,224]
Neo-angiogenesis	a. Inhibit the infiltration of effector immune cells b. Upregulate the expression of PD-L1 c. Recruit Treg, TAM, and MDSC cells d. Impair the delivery of therapeutic agents to tumor cells e. Reduce adhesion molecules into TME	Hypoxia, HIF1-A, VEGFA, VEGFR, Angiopoietin-2 (ANG2)	[228,229]
High oxidative metabolism	a. Trigger hypoxia b. Promote cancer cell growth, proliferation, and metastasis c. Create immunosuppressive TME d. Affect effector T cells	OXPHOS complexes, heme, HIF1-A, VEGFA, VEGFR	[179,180,230,231,232]
Immunosuppressive TME	a. Recruit immunosuppressive cells (Tregs, Bregs, MDSCs, TAM, and CAF) b. Inhibit the infiltration of the effector immune cells c. Release of proinflammatory molecules d. Upregulate immune checkpoint proteins (ICPs) e. Affect antitumor immunity	Alternative ICPs, immunosuppressive molecules, proinflammatory molecules, VEGFA, HIF1-A	[228,233,234]
Upregulation of alternative immune checkpoints	a. Modulate TME and show adaptive resistance to anti-PD-1	LAG-3, TIGIT, TIM3, and TIM-1	[228,234]
Deregulated epigenetics	a. Modify the expression of immune related genes b. Triggers T-cell dysfunction	DNA methyl transferase; histone methyl transferase; histone deacetylase	[215,218]
Dysregulated circRNAs	a. Upregulate PD-L1 b. Recruit inflammatory molecules c. Inhibit the CD8+ T cells’ infiltration into tumorigenic regions	hsa_circ_0000190, hsa_circ_0079587, circFGFR1, circUSP7	[235,236,237,238,239]
Modified gut microbiota	a. Reduce effector T cells b. Increase regulatory T cells c. Affect antitumor responses	Gut microbiota composition; gut bacteria	[240]