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<p>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.</p> Graphical abstract <p></p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月24日

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  • 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

摘要

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.

Graphical abstract