LAUSR

Obesity is the second leading modifiable risk factor for many cancers, behind only smoking. It can, however, also provide a benefit and increase responses and outcomes to checkpoint immune therapies. To understand this paradox and improve cancer immunotherapy, we examined the tumor immune microenvironment of lean and obese animals and human subjects. Interestingly, we found that the immune suppressive receptor PD-1 was upregulated on tumor associated macrophage with obesity. PD-1 directly suppressed macrophage metabolism and ability to phagocytose targets and stimulate T cells. Blockade or genetic deletion of PD-1, however, released macrophages from this suppression and allowed robust anti-tumor activity. These data define a mechanism of the obesity-cancer paradox and point to obesity-induced inflammation as a modifier of tumor associated macrophages that could be exploited to broadly improve immune therapy outcomes. Jeffrey C. Rathmell, Jackie E. Bader. Inflammatory drivers of the obesity-cancer connection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY21-02.