Obesity shapes a reversible immune microenvironment that fosters 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-alpha, 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.