Effects of Tirzepatide on Tumor Microenvironment in Obesity-Associated Breast Cancer

Numerous anti-obesity agents have been approved for obesity/diabetes treatment, but their impact on obesity-related breast cancer is not clear. Our pilot data supported a trend for reduced growth of estrogen-receptor positive (ER+) tumors with tirzepatide (TZP), an FDA-approved incretin mimetic targeting both GLP-1 and GIP receptors. Here, our goal was to determine if TZP-induced changes in the mammary tumor microenvironment contributed to the anti-cancer effects of TZP. Female C57/BL6 mice were fed a 46% high-fat diet to induce obesity. They were then randomized to receive tirzepatide (15-week dose escalation to 75nM) or vehicle for the duration of the study. Three weeks after starting TZP, tumors were initiated by injection of estrogen-receptor positive Py230 cells, and tumor volumes were measured twice weekly. Mice were terminated when tumor volumes reached humane endpoints, or after 16 weeks of treatment. Mammary adipose tissue was collected at the end of the study and processed for histological examination. Adipocyte size was assessed in H&E stained tissues using the Adiposoft plugin for ImageJ, and number of macrophages in the tumor microenvironment was assessed using Mac2 immunofluorescence staining. As expected, TZP induced ∼20% weight loss, which was reflected in both an increase in the proportion of small adipocytes and a reduction in the number of large adipocytes in the tumor microenvironment (mammary gland). This suggests that changes in macrophage infiltration are not likely to contribute to the potential anti-cancer effects of TZP in our pilot studies. Ongoing studies will address additional mechanisms by which TZP affects tumors and/or the obese tumor microenvironment. Citation Format: Charlotte E. Gibson, Amanda L. Kucinskas, Emma G. Bailey, Flora Tao, Katherine E. Sanchez, Katherine L. Cook, Erin D. Giles. Effects of the anti-obesity medication tirzepatide on the tumor microenvironment in a mouse model of obesity-associated, hormone-dependent breast cancer [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 3623.