Table 1.

Summary of Known Resistance Mechanisms to Checkpoint Inhibitors

Categories of Resistance	Mechanism of Resistance
Tumor intrinsic factors	Downregulation of antigen processing and presentation: HLA deletion144,145, β2 microglobulin146
	Downregulation of cytokines and signaling pathways: loss of JAK1/2 function69,147, deletion of interferon IFNGR1/2, IRF1 148
	β-Catenin activation (due to mutations in CTNNB1 gene)73
Tumor extrinsic factors	TILs exclusion by PTEN deletion and VEGF upregulation149
	Expression of alternative coinhibitory checkpoint receptors like TIM-3, LAG-3, TIGIT, VISTA, and BTLA69,126
	Decreased TILs to Treg ratio150–152
	Downregulation of dendritic cell recruitment through β-catenin signaling110
	Increased immunosuppressive cells such as MDSCs, Tregs151,153,154
	Epithelial-to-mesenchymal transition155
	Microbiome75, 143