Fatty acids in the tumor microenvironment reprogram neutrophils to induce immunosuppression via adenosine
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.
Authors
- Peter Sajjakulnukit (ORCID: https://orcid.org/0000-0002-8556-7481)
- James Moon (ORCID: https://orcid.org/0000-0001-8071-1491)
- Carole A. Parent (ORCID: https://orcid.org/0000-0002-1518-1452)
- Eileen S. Carpenter (ORCID: https://orcid.org/0000-0001-6775-6943)
- Nikhil Kumar Kotla (ORCID: https://orcid.org/0000-0003-0616-9141)
- Shogo Takahashi (ORCID: https://orcid.org/0000-0002-3831-5353)
- Subhash B. Arya (ORCID: https://orcid.org/0000-0002-5671-8666)
- Elena M. Stoffel (ORCID: https://orcid.org/0000-0002-5637-3418)
- Ryan J. Rebernick (ORCID: https://orcid.org/0000-0002-5532-581X)
- Prarthana Dalal (ORCID: https://orcid.org/0000-0001-5812-088X)
- Rashi Singhal (ORCID: https://orcid.org/0000-0003-2685-5667)
- Sumeet Solanki (ORCID: https://orcid.org/0000-0002-2773-3082)
- Hannah N. Bell (ORCID: https://orcid.org/0000-0003-2609-5557)
- Carlos Ichiro Kasano-Camones
- Wesley Huang (ORCID: https://orcid.org/0000-0003-0551-8397)
- Andrew D. Patterson (ORCID: https://orcid.org/0000-0003-2073-0070)
- Weiping Zou (ORCID: https://orcid.org/0000-0001-7952-3549)
- Himani Jasewicz
- Frank J. Gonzalez
- Marina Pasca di Magliano
- Yatrik M Shah
- Zheng Hong Lee
- Costas A Lyssiotis
- Michael D Green
Institutions
- National Institutes of Health (US)
- Pennsylvania State University (US)
- University of Michigan (US)
- Michigan Cancer Research Consortium (US)
- BioSurfaces (United States) (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-06
- DOI
- https://doi.org/10.64898/2026.04.02.716169
- Primary Topic
- Adenosine and Purinergic Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00