Fatty acids in the tumor microenvironment reprogram neutrophils to induce adenosine-mediated immunosuppression in mice

As solid tumors progress, the tumor microenvironment becomes increasingly immunosuppressive, impairing cytotoxic T-cell activity and limiting the efficacy of immune checkpoint blockade. However, the mechanistic drivers of this immunosuppression remain poorly understood. Here, we identify a tumor-derived lipid–neutrophil–adenosine axis as a critical regulator of immune suppression in advanced colorectal cancer (CRC). We show that fatty acids enriched in tumor interstitial fluid reprogram neutrophils toward an immunosuppressive phenotype through PPARα activation, upregulation of CD39 and CD73, and adenosine generation, ultimately leading to T-cell suppression. AB928, a dual A2aR/A2bR adenosine receptor antagonist currently in clinical trials, restores T-cell proliferation, effector function, and tumor-killing capacity in vitro and in vivo. Importantly, AB928 synergizes with anti-PD-1 therapy to enhance survival in an immunotherapy-resistant autochthonous model of metastatic CRC. Thus, our findings define a metabolic immune evasion mechanism in the microenvironment and provide a rationale for targeting neutrophil-derived adenosine signaling to improve immunotherapy responses in CRC. 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.