OBESITY AND SEX IN CANCER IMMUNOTHERAPY

Obesity is a multifaceted condition often associated with poor outcomes in cancer, yet clinical evidence suggests that obese patients may benefit disproportionately from immunotherapy respect to the lean population. The mechanisms underlying this phenomenon, particularly in relation to sex, remain unclear. In this thesis, I investigated the impact of obesity and sex on tumor progression and response to anti–PD-1 therapy. Using the MC38 murine colorectal cancer model, we observed that high-fat diet (HFD) feeding accelerated tumor growth in both sexes, but more prominently in males. Nevertheless, the therapeutic benefit of anti–PD-1 was greatest in obese males, whose tumors exhibited markedly reduced progression compared to lean counterparts. These results align with clinical trends indicating improved outcomes in obese male patients, while highlighting sexually dimorphic effects of obesity on tumor immunity. To strengthen the robustness of our preclinical platform, we optimized the in vivo tumor model and applied a novel computational anti-clustering algorithm for animal randomization, which reduced baseline imbalances and enhanced reproducibility. My results revealed that macrophages, rather than CD8⁺ T cells alone, were the most consistently remodeled population in the tumor microenvironment, showing sex- and obesity-dependent infiltration. In vitro studies further demonstrated that lipid excess and estrogen differentially shaped macrophage inflammatory and antigen-presenting functions across sexes, with IL-6 emerging as a candidate mediator linking metabolic stress and immune regulation. Our findings provide mechanistic insight into how sex and obesity interact to modulate cancer immunotherapy, highlighting macrophages as central regulators of these effects, and underscore the importance of considering host-intrinsic factors in both preclinical modeling and the design of personalized immunotherapeutic strategies.