Table 2.

Mechanisms of resistance to immunotherapy.

Type of resistance	Category	Factor	Relation	References
Primary resistance to immunotherapy	Patient-intrinsic factor	Immunosenescence	Aging limits immune response	[96,97,98,99,100]
		HLA genotype	Homozygosity in at least one HLA-I locus is associated with poor response to ICIs	[101,102]
		Host microbiome	Changes in diversity and abundance of host microbiome modify the response to ICIs	[103,104,105]
	Tumor cell-intrinsic factor	Downregulation of HLA expression	Loss of HLA-I expression reduces T-cell response	[106,107]
		Alteration of oncological signaling pathways	Abnormal expression of MAPK pathway, loss of PTEN, constitutive WNT/β-catenin expression, JAK1/2 mutations and loss of IFN-γ are involved in resistance to ICIs	[108,109,110,111,112,113,114,115]
	Tumor cell-extrinsic factor	Inadequate T-cell infiltration	Absence of T cells near the tumor reduces T cell response	[116]
		Presence of immunosuppressive cells	High level of infiltration of Treg, MDSCs and TAM suppress T-cell activation and is correlated with poor prognosis and resistance to ICIs	[117,118,119,120,121,122,123,124,125]
Acquired resistance to immunotherapy	Tumor cell-intrinsic factor	Changes in HLA expression	Mutations in β2-microglobulin are associated with acquired resistance to ICIs	[126,127,128,129,130,131]
		Defects of IFN-γ signaling	Escape mutations in IFN-γ pathway result in loss of HLA-I and PD-L1 expression and ICI resistance	[128,132]
		Mutations in genes that encode tumor neoantigens	Mutations in genes that encode tumor neoantigens reduce tumor recognition by immune system, leading to immune evasion and clinical progression	[133,134]
		Upregulation of other immune checkpoint receptors	Upregulation of TIM3 and LAG	[135]
		Alteration of oncological signaling pathways	Loss of PTEN and increase in WNT/β-catenin expression are linked to acquired resistance	[136]