Fatty acids in the tumor microenvironment reprogram neutrophils to induce adenosine-mediated immunosuppression in mice
Year: 2026
Type: article
Abstract: As solid tumors progress, the tumor microenvironment (TME) becomes increasingly immunosuppressive, impairing cytotoxic T-cell activity and limiting the efficacy of the 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 to generate adenosine via PPARα activation, leading to T-cell suppression. Using AB928, a dual A2aR/A2bR adenosine receptor antagonist currently in clinical trials, we restored T-cell proliferation, effector function, and tumor-killing capacity in vitro and in vivo. Importantly, AB928 synergized with anti-PD-1 therapy to enhance survival in an autochthonous model of metastatic CRC. Our findings define a metabolic immune evasion mechanism in the TME and provide a rationale for targeting neutrophil-derived adenosine signaling to improve immunotherapy responses in CRC and other solid tumors.
Source: Nature Communications
Authors: Rashi Singhal, Nina W. Zhang, Zheng Hong Lee, Hannah N. Bell, Prarthana J. Dalal, Sumeet Solanki, Wesley Huang, Ryan Rebernick, Peter Sajjakulnukit, Himani Jasewicz, Roshan Kumar, Nikhil Kumar Kotla, Amanda K. Huber, Mallappa Anitha, Liliane Morath, Subhash B. Arya, Shogo Takahashi, Carlos Ichiro Kasano-Camones, Eileen Carpenter, Marina Pasca di Magliano, James J. Moon, Carole A. Parent, Frank J. Gonzalez, Andrew D. Patterson, Michael D. Green, Weiping Zou, Elena M. Stoffel, Costas A. Lyssiotis, Yatrik M. Shah
Language: English
Subfield: Physiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: Role of Macrophage HIF2 alpha in inflammatory mechanisms of Atherosclerosis, Understanding the mechanisms of iron addiction in colon cancer, Defining the role of microenvironmental ammonia in colorectal cancers, G3401190142, The role of lipid reprogramming in ferroptotic cell death in inflammatory bowel disease (IBD), G4961766164, G5198034117, Stromal metabolism promotes therapeutic resistance in pancreatic cancer, Signal relay during directed cell migration, Control of iron absorption by intestinal HIF2 in iron and hematological disorders, University of Michigan Rogel Cancer Center Support Grant 2023-2028, The role of HIF2alpha in colon carcinogenesis, Xenobiotic receptors, Oncology Research Training Grant, Ablating Liver Metastases with SBRT to Enhance Immune Checkpoint Blockade in Melanoma
OpenAlex ID: W7223065228