Abstract Remarkable progress in cancer immunotherapy has revealed the power of harnessing immunity to combat cancer. Anti-tumor T cells suppress tumor development by secreting cytotoxic cytokines and activating other immune cells. However, the tumoricidal function of tumor-infiltrating T cells is often suppressed and inefficient to combat tumors. Thus one of the key questions in the field of cancer immunology is to address what causes the immunosuppressive nature of the tumor microenvironment. Using a melanoma mouse model, we found that 1) fatty acids accumulated in the tumor microenvironment, 2) unsaturated fatty acids suppressed T cell effector function through CD36/PPAR pathway and 3) blocking FAs transportation into T cells enhanced T cell cytotoxicity and delayed tumor growth. This study has identified unsaturated fatty acid species as immunosuppressive factors in tumor, which may lead to the development of novel forms of therapy that stimulates anti-tumor immunity by manipulating fatty acid transportation and metabolism.