Fatty acids in the tumor microenvironment reprogram neutrophils to induce adenosine-mediated immunosuppression in mice
Menée à l'aide de lignées cellulaires et d'un modèle murin de cancer colorectal métastatique, cette étude met en évidence un mécanisme par lequel les acides gras du microenvironnement tumoral favorisent la suppression des lymphocytes T en modifiant le phénotype des neutrophiles via l'activation des récepteurs PPAR-alpha, la surexpression des marqueurs CD39 et CD73 et la synthèse d'adénosine, puis met en évidence l'intérêt d'un antagoniste des récepteurs A2aR/A2bR pour restaurer la prolifération et la fonction effectrice des lymphocytes T
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.
Nature Communications , résumé, 2026