Table 2.

Mechanisms of response and resistance

Pathway	Genes	Mechanism	References
TMB and neoantigen load		Low mutational load results in lack of antigenic proteins, and increased subclonal mutation/neoantigen loads are associated with poor response	[31–33, 36]
DNA damage repair	• MSH2 • MSH6 • PMS2 • POLE • BRCA2	Mutations in DDR genes result in increased TMB and genomic instability, which can result in a highly antigenic and immunogenic tumor	[21, 44–46]
MAPK pathway	• KRAS • STK11 • TP53	Oncogenic expression reduces TILs and pro-inflammatory cytokines. Activation of downstream pathways may also play a role in immunotherapy response (for example, p38 and JNK)	[57–59]
PI3K-AKT-mTOR pathway	• PTEN	Loss of PTEN causes oncogenic expression of PI3K pathway, which reduces TILs	[63–66]
WNT-β-catenin pathway	• DKK2	β-catenin suppresses chemokines that recruit DCs to the TME, and activation of DKK2 suppresses T cells and NK cells	[71, 72]
IDO1 pathway	• IDO1	Expression of IDO1 promotes activation of the PI3K pathway and immunosuppression	[73–75]
HLA variability	• B2M	Loss of HLA heterozygosity associated with decreased survival, and LoF mutations in antigen presentation genes (for example, B2M) can result in tumor evasion of immune response. Certain HLA supertypes are also associated with improved response (for example, HLA-B44) compared to others (for example, HLA-B62)	[76, 78, 79]
JAK-STAT pathway	• IFNGR1 • JAK1 • JAK2 • JAK3 • ALPNR • SOCS1	Lack of JAK-STAT signaling results in resistance to immunotherapy through suppression of IFNγ	[88, 90–93]
TGFβ		Expression of TGFβ enhances the function of Tregs, limiting the infiltration of T cells in the TME. TGFβ also downregulates the activity of cytotoxic lymphocytes and NK cells	[95, 96]
Chromatin remodeling	• ARID1A • PBRM1 • SMARCA4 • EZH2	Loss of BAF/PBAF or EZH2–PRC2 complex induces IFNγ expression. Naturally, PRC2 interacts with PBRM1 of the PBAF complex to suppress IFNγ-stimulated genes	[103–107]
Endogenous retroviruses		Upregulation of ERV genes primes the innate immune system. Several epigenetic mechanisms can increase expression of ERV genes, which leads to an elevated abundance of double-stranded RNA, and thus immune response. Such mechanisms include LoF in histone demethylases (for example, LSD1), histone deacetylases, or DNA methyltransferases	[109–111]
Urea cycle		UC dysregulation causes purine-to-pyrimidine transversion mutational bias that generates hydrophobic, highly immunogenic neoantigens	[112–114]
Microbiome		Gut microbiome composition affects T cell abundance in TME, and thus response to ICB (for example, higher levels of Ruminococcaceae in responders and higher levels of Bacteroidales in non-responders)	[115–117]

DDR DNA damage repair, ERV endogenous retrovirus, HLA human leukocyte antigen, ICB immune checkpoint blockade, LoF loss of function, MHC major histocompatibility complex, NK natural killer, TIL tumor infiltrating lymphocyte, TMB tumor mutational burden, TME tumor microenvironment, UC urea cycle