Cancer is a leading cause of human disease. Avoiding cancer immune surveillance and metabolic reprogramming are the two newly added hallmarks of cancer, but requiring more mechanistic understanding and effective coping strategies. Our data show that pristanic moieties, including pristane, a natural immunostimulant inspired by the diet of cancer resistant whales, and its optimized derivatives, elevate MHC II expression to potentiate immune detection and cancer destruction by binding to the substrate pocket in the MAT domain of FASN and inhibiting fatty acid synthesis. This study improves our mechanistic understanding of immunity and metabolism in cancer as well as provides metabolic immunotherapies by revealing the critical role of metabolism-silenced MHC II exerted by pristane moieties in cancer immune detection.