VSIR and neoplasm: We are cognizant that loss of IFN-γ signaling is one of the mechanisms of resistance to ICBs, which can be derived from other intrinsic alterations in tumor cells (such as active β-catenin and PTEN loss), stroma factors (eg, infiltration of immunosuppressive Treg and myeloid-derived suppressor cells, as well as expression of multiple inhibitory checkpoints (CTLA-4, PD-1/PD-L1, LAG-3, TIGIT, TIM-3, VISTA, etc.), and host characteristics (eg, microbiota composition).