Investigating Potential Mechanisms Underlying the Anticancer Benefit of Tirzepatide-Induced Weight Loss

Obesity is a well-established risk and prognostic factor for many different types of cancer. Therefore, weight loss may be a promising way to indirectly reduce cancer progression. We have previously shown that the weight-loss drug tirzepatide, a dual glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide (GIP) receptor agonist, induces adipose tissue reduction and improved metabolic outcomes that significantly slowed tumor growth, but the mechanism(s) driving this anticancer benefit remains unclear. Here, we assessed whether tirzepatide normalized adipose morphology and function.in association with an anti-tumoral immune response. To address our aims, tissue samples were collected from tumors and tumor-adjacent subcutaneous adipose tissue in lean mice, diet-induced obese mice, and formerly diet-induced obese mice treated with tirzepatide. RNA was extracted from the tumors, reverse transcribed, and then the expression of specific genes related to immune lineage and function was quantified using qPCR. To measure changes in adipose morphometry, we applied a novel automated segmentation method to formalin-fixed and paraffin-embedded adipose tissue samples stained with hematoxylin and eosin. We found no evidence of tirzepatide impacting the intertumoral expression of genes related to immune lineage and function. However, tirzepatide treatment significantly reduced adipocyte area while increasing adipocyte density relative to untreated obese mice, though adipocytes remained larger in tirzepatide-treated mice than in lean mice. The reduction in adipocyte hypertrophy is correlated with reduced tumor growth and therefore may be one anticancer benefit of tirzepatide treatment. These findings underscore the potential of tirzepatide as a therapeutic strategy to mitigate obesity-associated cancer risk and progression.