Table 1. . Potential mechanisms of PD-1 inhibitor resistance in somatic mismatch repair cancers.

Resistance pathway	Hypothesized mechanism of action	Ref.
Tumor mutational burden and neoantigen load	Low mutational load results in lack of antigenic proteins and increased subclonal mutation/neoantigens loads are associated with poor response. Adaptive resistance may occur with variation of neoantigen repertoire	[9,74,75]
PTEN loss	Loss of PTEN causes oncogenic expression of PI3K pathway, which reduces tumor infiltrating lymphocytes	[76]
Upregulation of compensatory checkpoints (LAG3)	Increased expression is accompanied by decreased T-cell effector function; as an immune inhibitory molecule, synergistically interacts with PD-1 to regulate T-cell function to promote tumoral immune escape	[77,78]
JAK1 and JAK2 mutations	Inactivation of JAK1 or JAK2 allows cancer cells to escape immune recognition via receptor-level signaling bottlenecks – selectively blocks IFN-γ signaling that leads to cell-growth inhibition	[79]
CTNNB1/Wnt/β-catenin mutations	Gain of function mutation potentially mediates acquired resistance by excluding T cells from immune activation. Tumors in which this pathway is active are relatively ‘cold’ and less likely to respond to PD-1/PD-L1	[80,81]
Expression of MHC antigens	MHC is significantly downregulated in anti-PD-1 resistant tumors. Multiple routes to loss of expression. Whereas β-2-microglobulin mutations predominate in Lynch syndrome, the inactivation of various antigen-presenting machinery components differs in sporadic cancers. Different expression levels affect the ability of natural killer T-cells to engage tumor cells	[82,83]
β-2-microglobulin mutations	Loss of function mutations alter antigen presentation genes can result in tumor evasion of immune response. β-2-microglobulin is responsible for proper MHC class I folding and transport to cell surface required for CD8+ T-cell recognition	[84,85]
Overexpression of TGFβ	Expression of TGFβ enhances the function of T-regulators, limiting the infiltration of T cells. TGFβ also downregulates the activity of cytotoxic lymphocytes and natural killer cells	[86,87]