Figure 3.

Schematic presentation of the intrinsic tumor factors associated with resistance to immunotherapy. Multiple mechanisms of cancer resistance to immunotherapy, including (I) loss of neoantigen due to the dedifferentiation or lack of antigen mutations, or mutations in IFN signaling; (II) abnormalities in antigen processing, such as endoplasmic reticulum stress, proteosomes, and TAP protein disturbances; (III) aberrant signaling due to the fact of genetic mutations, such as MAPK, PI3, Wnt/β catenin, and interferon JAK1,2/STAT pathways; (IV) abnormalities in antigen presentation due to the loss of MHC-1 expression, nonclassical MHC-I expression, or β2 microglobulin mutations; (V) expression or exocytosis of immune checkpoint proteins, such as PD-L1; (VI) secretion of metabolites by cancer cells, such as adenosine, epoxy cholesterol, hydroxy cholesterol, and kynurenine, in addition to hypoxia and acidosis, leading to the modulation of the tumor microenvironment; (VII) epigenetic reprogramming of cancer cells through stemness transformation or EMT changes; (VIII) resistance to apoptosis by the aberrant expression of intrinsic and extrinsic apoptotic proteins; (IX) mitochondrial disturbances due to mutations in cytochrome proteins or enzymes in the tricyclic-acetic-acid cycle. Created with BioRender.com.