SUMMARY: Our understanding of the mechanisms used by the host immune system to fight growing tumors has increased exponentially in recent decades, ushering in the development of new therapeutic approaches such as immune checkpoint blockade (ICB) that have revolutionized cancer treatment. Despite these advances, many patients fail to respond to even the most promising immunotherapies. Thus, there persists an urgent need to identify the host factors responsible for the limited efficacy of these otherwise potent immunotherapies in cancer patients. Not surprisingly, identifying mechanisms of immunotherapy resistance is an active area of research. However, the vast majority of pre-clinical and clinical studies in this area do not take into account the effects of common patient co-morbidities like obesity. This is notable because it is estimated that by 2050 half of all adults in the U.S. will have obesity (defined as a Body Mass Index (BMI) of >30 kg/m2). Studies focused on understanding the impact of obesity on anti-tumor immunity and cancer immunotherapy outcomes have grown dramatically in number. However, the field still lacks a clear understanding of when obesity is beneficial for cancer patients, when it is not, and why. Renal cancer is one of 13 tumor types whose prevalence is increased by obesity. Multiple independent studies have found that even in advanced renal cancer patients, 50-60% display BMI-defined overweight or obesity at ICB treatment initiation. Thus, identifying the biological drivers of obesity-associated ICB resistance versus susceptibility in renal cancer is a critically important area of research that could directly impact the majority of patients battling this disease. We have been studying ICB resistance in the context of host obesity. We retrospectively examined outcomes in a cohort of renal cancer patients who received standard of care anti-PD-1. In patients with BMI-defined obesity at treatment initiation, 67% exhibited cancer progression at 12 months, whereas the remaining 33% were progression-free, illustrating the highly variable effects of host obesity on patient outcomes. This trend was reflected in our pre-clinical model of orthotopic renal cancer, in which we found that host obesity is linked to cancer progression in 56% of mice that received an anti-PD-1-based combinatorial immunotherapy. Here we will combine pre-clinical murine and prospective human subject studies to test the hypothesis that sustained high levels of IL-1b inflammation during ICB therapy are associated with poor outcomes in renal cancer patients who have obesity. We further predict that blockade of intratumoral IL-1b will result in a favorable remodeling of the renal TME and improve ICB outcomes. Our findings will permit a more nuanced understanding of the obesity-associated mediators of ICB resistance in renal cancer patients, thereby: 1) providing new metrics to use for identifying patients who are less likely to respond to ICB and 2) facilitati...