Obesity is a well-established risk factor for cancer, but the underlying mechanisms are not fully understood. This study investigates the impact of obesity-related T cell dysfunction on cancer risk and immune surveillance using a mouse model of diet-induced obesity. Key findings include: 1. **T Cell Dysfunction in Obese Mice**: CD8+ T cells in obese mice exhibit impaired effector function compared to lean mice, leading to reduced tumor control even after immune checkpoint blockade (ICB) therapy. 2. **Diet-Induced Weight Loss**: Obese mice that lose weight through dietary changes show restored CD8+ T cell function and improved responses to ICB therapy, suggesting that dietary intervention can reverse obesity-related immune dysfunction. 3. **Semaglutide-Induced Weight Loss**: While semaglutide-induced weight loss in obese mice is effective, it does not significantly improve liver health or other metabolic comorbidities, and thus does not fully restore immune function. 4. **Cancer Risk and Immune Dysfunction**: Obese mice exposed to a chemical carcinogen develop sarcomas at higher rates than lean mice, indicating that compromised immune surveillance contributes to increased cancer risk. 5. **Tumor Immunoediting**: Tumors from obese mice show altered immunoediting, leading to more immunogenic tumors that are more sensitive to ICB therapy. 6. **Conclusion**: The study provides insights into the complex interplay between obesity, immunity, and cancer, suggesting that restoring immune function through weight loss may be a potential strategy to improve cancer outcomes in obese patients.Obesity is a well-established risk factor for cancer, but the underlying mechanisms are not fully understood. This study investigates the impact of obesity-related T cell dysfunction on cancer risk and immune surveillance using a mouse model of diet-induced obesity. Key findings include: 1. **T Cell Dysfunction in Obese Mice**: CD8+ T cells in obese mice exhibit impaired effector function compared to lean mice, leading to reduced tumor control even after immune checkpoint blockade (ICB) therapy. 2. **Diet-Induced Weight Loss**: Obese mice that lose weight through dietary changes show restored CD8+ T cell function and improved responses to ICB therapy, suggesting that dietary intervention can reverse obesity-related immune dysfunction. 3. **Semaglutide-Induced Weight Loss**: While semaglutide-induced weight loss in obese mice is effective, it does not significantly improve liver health or other metabolic comorbidities, and thus does not fully restore immune function. 4. **Cancer Risk and Immune Dysfunction**: Obese mice exposed to a chemical carcinogen develop sarcomas at higher rates than lean mice, indicating that compromised immune surveillance contributes to increased cancer risk. 5. **Tumor Immunoediting**: Tumors from obese mice show altered immunoediting, leading to more immunogenic tumors that are more sensitive to ICB therapy. 6. **Conclusion**: The study provides insights into the complex interplay between obesity, immunity, and cancer, suggesting that restoring immune function through weight loss may be a potential strategy to improve cancer outcomes in obese patients.