Evidence map›Paper›PMID 41993509›Full record

ArticlebioRxiv : the preprint server for biology2026

Fatty acids in the tumor microenvironment reprogram neutrophils to induce immunosuppression via adenosine.

Rashi Singhal, Nina W Zhang, Zheng Hong Lee, Hannah N Bell, Prarthana J Dalal, Sumeet Solanki, Wesley Huang, Ryan Rebernick, Peter Sajjakulnukit, Himani Jasewicz and 18 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

28 authors.

Rashi SinghalDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Nina W ZhangDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID 0009-0007-8012-0246
Zheng Hong LeeDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Hannah N BellDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Prarthana J DalalDepartment of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA.
Sumeet SolankiDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Wesley HuangProgram in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA.
Ryan RebernickDepartment of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Peter SajjakulnukitRogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.ORCID 0000-0002-8556-7481
Himani JasewiczCancer Biology Graduate Program, University of Michigan, Ann Arbor, MI.ORCID 0009-0000-9802-4497
Roshan KumarDepartment of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA.
Nikhil K KotlaDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Amanda HuberDepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
Anitha Vijay MallappaDepartment of Veterinary and Biomedical Sciences, College of Agricultural Sciences, Penn State University, PA, USA.
Subhash B AryaLife Sciences Institute, University of Michigan, Ann Arbor 48109, USA.ORCID 0000-0002-5671-8666
Shogo TakahashiCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Carlos Ichiro Kasano-CamonesCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.ORCID 0009-0000-6684-7472
Eileen CarpenterRogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.ORCID 0000-0001-6775-6943
Marina Pasca di MaglianoRogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
James J MoonRogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Carole A ParentRogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.ORCID 0000-0002-1518-1452
Frank J GonzalezCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Andrew D PattersonDepartment of Veterinary and Biomedical Sciences, College of Agricultural Sciences, Penn State University, PA, USA.ORCID 0000-0003-2073-0070
Michael D GreenRogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Weiping ZouRogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Elena M StoffelDepartment of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA.ORCID 0000-0002-5637-3418
Costas A LyssiotisDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID 0000-0001-9309-6141
Yatrik M ShahDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.ORCID 0000-0002-2487-4816

Funding

XenograftP30CA046592 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Eric R. Fearon · 1988 to 2026
$178.2M
Xenobiotic receptorsZIABC005562 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI GONZALEZ, FRANK J · 2009 to 2025
$26.9M
ONCOLOGY RESEARCH TRAINING GRANTT32CA009357 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Qing Li · 1987 to 2026
$8.6M
Control of iron absorption by intestinal HIF2 in iron and hematological disordersR01DK095201 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2012 to 2025
$5.7M
The role of HIF2alpha in colon carcinogenesisR01CA148828 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2010 to 2025
$5.2M
Signal relay during directed cell migrationR01AI152517 · NIAID · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI HANSON, PHYLLIS I, PARENT, CAROLE ANNE · 2020 to 2024
$2.6M
Understanding the mechanisms of iron addiction in colon cancerR01CA245546 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2020 to 2024
$2.3M
Ablating Liver Metastases with SBRT to Enhance Immune Checkpoint Blockade in MelanomaR01CA276217 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI THEODORE S LAWRENCE · 2023 to 2026
$2.2M
Stromal metabolism promotes therapeutic resistance in pancreatic cancerR01CA248160 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI LYSSIOTIS, COSTAS ANDREAS · 2020 to 2024
$2.0M
The role of lipid reprogramming in ferroptotic cell death in inflammatory bowel disease (IBD)F30DK131851 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI HUANG, WESLEY WEIQIAO · 2022 to 2023
$80k
Defining the role of microenvironmental ammonia in colorectal cancersF30CA257292 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BELL, HANNAH NOELLE · 2021 to 2022
$40k
BLRD VA I01 BX005267Intramural NIH HHS ZIA BC005562NCI NIH HHS F30 CA257292NCI NIH HHS P30 CA046592NCI NIH HHS R01 CA148828NCI NIH HHS R01 CA245546NCI NIH HHS R01 CA248160NCI NIH HHS R01 CA276217NCI NIH HHS T32 CA009357NIAID NIH HHS R01 AI152517NIDDK NIH HHS F30 DK131851NIDDK NIH HHS R01 DK095201
6 · The paper itself

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.

Indexed as

adenosinefatty-acidsNeutrophilsT cellsTME

Identifiers

PMID41993509
PMCPMC13081818

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.