The nonsteroidal anti-inflammatory drug sulindac reverses obesity-driven immunosuppression and triple-negative breast cancer progression

Michael F Coleman; Shannon B McDonell; Lydia K Eisenbeis; Emily N Devericks; Jobin Chandi; Om Dave; Jane B Pearce; Sylvia Wang; Morgan Cody; Ximena M Bustamante-Marin; Elaine M Glenny; Erika T Rezeli; Alyssa J Cozzo; Ciara H O'Flanagan; Brooke E Bathon; Saame Raza Shaikh; Ginger L Milne; Michael K Wendt; Nadia A Lanman; Dorothy Teegarden; Stephen D Hursting

doi:10.1186/s13058-025-02134-2

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The nonsteroidal anti-inflammatory drug sulindac reverses obesity-driven immunosuppression and triple-negative breast cancer progression

Journal article

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The nonsteroidal anti-inflammatory drug sulindac reverses obesity-driven immunosuppression and triple-negative breast cancer progression

Michael F Coleman, Shannon B McDonell, Lydia K Eisenbeis, Emily N Devericks, Jobin Chandi, Om Dave, Jane B Pearce, Sylvia Wang, Morgan Cody, Ximena M Bustamante-Marin, …

Breast cancer research : BCR, Vol.27(1), 186

10/24/2025

DOI: 10.1186/s13058-025-02134-2

PMCID: PMC12551206

PMID: 41137072

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Abstract

Obesity affects over 40% of women in the US and increases the risk and progression of several cancers, including triple-negative breast cancer (TNBC), in part through chronic low-grade inflammation and impaired antitumor immunity. While weight loss can reverse obesity-driven cancer risk, cost and other factors limit the accessibility of effective weight loss interventions. This study investigated whether sulindac, a nonsteroidal anti-inflammatory drug (NSAID), could mitigate obesity-driven TNBC progression. Using multiple preclinical models, we demonstrate that sulindac treatment abrogates obesity-accelerated tumor growth and metastasis without affecting body weight or composition. Bulk transcriptomic profiling revealed obesity-driven suppression of immune-related gene signatures in the tumor microenvironment (TME)—including antigen presentation—while sulindac treatment restored these signatures. Single-cell RNA sequencing identified sulindac-mediated reprogramming of tumoral metabolism toward oxidative phosphorylation and restoration of antigen presentation machinery in tumor-associated macrophages. Sulindac also reversed obesity-driven reduction in T cell receptor diversity within the TME. We conclude that sulindac treatment remodels the TME and restores obesity-associated impairments of immunosurveillance, offering a potentially accessible intervention to limit obesity-driven TNBC progression. We demonstrate that NSAIDs, which are generally safe, cheap, and readily available, limit the burden of obesity-driven TNBC preclinically, warranting further evaluation as a targeted clinical intervention.

Inflammation

Obesity

Antitumor immunity

Tumor microenvironment

TNBC

Details

Title: Subtitle: The nonsteroidal anti-inflammatory drug sulindac reverses obesity-driven immunosuppression and triple-negative breast cancer progression
Creators: Michael F Coleman - University of North Carolina at Chapel Hill
Shannon B McDonell - University of North Carolina at Chapel Hill
Lydia K Eisenbeis - University of North Carolina at Chapel Hill
Emily N Devericks - University of North Carolina at Chapel Hill
Jobin Chandi - University of North Carolina at Chapel Hill
Om Dave - University of North Carolina at Chapel Hill
Jane B Pearce - University of North Carolina at Chapel Hill
Sylvia Wang - University of North Carolina at Chapel Hill
Morgan Cody - University of North Carolina at Chapel Hill
Ximena M Bustamante-Marin - University of North Carolina at Chapel Hill
Elaine M Glenny - University of North Carolina at Chapel Hill
Erika T Rezeli - University of North Carolina at Chapel Hill
Alyssa J Cozzo - University of North Carolina at Chapel Hill
Ciara H O'Flanagan - University of North Carolina at Chapel Hill
Brooke E Bathon - University of North Carolina at Chapel Hill
Saame Raza Shaikh - University of North Carolina at Chapel Hill
Ginger L Milne - Vanderbilt University
Michael K Wendt - Purdue University West Lafayette
Nadia A Lanman - Purdue University West Lafayette
Dorothy Teegarden - Purdue University West Lafayette
Stephen D Hursting - David H. Murdock Research Institute
Resource Type: Journal article
Publication Details: Breast cancer research : BCR, Vol.27(1), 186
DOI: 10.1186/s13058-025-02134-2
PMID: 41137072
PMCID: PMC12551206
NLM abbreviation: Breast Cancer Res
ISSN: 1465-542X
eISSN: 1465-542X
Publisher: BioMed Central
Grant note: R01CA271597 / NCI NIH HHS T32LM012420-02 / NCI NIH HHS P30CA023168 / NCI NIH HHS P30DK056350 / NIDDK NIH HHS BCRF-21-073 / Breast Cancer Research Foundation
Language: English
Date published: 10/24/2025
Academic Unit: Holden Comprehensive Cancer Center; Internal Medicine
Record Identifier: 9985019030302771

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