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

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.