Lipid accumulation in solid tumors supports tumor progression by promoting immune evasion. Yet the molecular basis of this lipid-mediated immunosuppression remains unclear. Here, using murine models of advanced colorectal cancer, the authors uncover a metabolic-immune axis whereby tumor-derived fatty acids activate neutrophil PPARα, resulting in adenosine generation and T cell suppression. Importantly, treatment with a dual adenosine receptor antagonist restores T cell-mediated antitumor immunity and synergizes with anti-PD-1 therapy to enhance animal survival.