Obesity Alters Immune Microenvironment to Promote Breast Cancer Growth

Obesity is linked to breast cancer risk and severity, yet the underlying mechanisms remain unclear. Using single-cell RNA sequencing, we identified a role for C1q+ macrophages in mammary tumors and adipose tissues in mouse obesity and breast cancer models. Macrophage-derived C1q promotes the clearance of obesity-associated apoptotic adipocytes, enhancing lipid metabolism and leading to an immunosuppressive tumor microenvironment via the production of prostaglandin E2 (PGE2). Moreover, the tumor-associated macrophages (TAMs) engage tumor cells in a feedforward loop by inducing the production of monocyte-recruiting cytokines further suppressing the anti-tumor immune response. Blockade of C1q, TNF-α, and PGE2 synthesis reduced tumor growth in obese mice. Importantly, weight loss via dietary changes or glucagon-like peptide-1 receptor (GLP-1R) agonism decreased C1q expression and suppressed obesity-driven tumor growth. Interference with the immunosuppressive environment and the feedforward loop may be viable strategies for improving the outcomes of breast cancer patients with obesity. Citation Format: Tao Zhang, Shimeng Liu, Yi Zhang, Alva Yijia Jiang, Zachary Sandusky, Na Zhang, Tara Akhshi, Nicole Traphagen, Jack Yueyang Wang, Lucas Tian, Esme Wheeler, Yingtian Xie, Rong Li, Buraq Ahmed, Genevra Kuziel, Capucine Heraud, Mohammed Mutaher, Henry Long, Kornelia Polyak, Myles A. Brown. Obesity shapes a reversible immune microenvironment that fosters breast cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6572.