HAVCR2 and cancer: Upregulation of immunosuppressive signaling pathways, such as PD-1, PD-L1, LAG-3 and TIM-3, infiltration of immunosuppressive cells, such as Treg cells, MDSC, M2 macrophages, a hypoxic and acidic environment, or metabolic alterations in the tumor microenvironment, have all been found to negatively contribute to anti-cancer immunity.