Project Summary/Abstract Background: Studies have revealed that obese individuals have longer survival on BRAF-targeted therapy (BRAF/MEKi) when compared to those with normal weight. This phenomenon, termed the "obesity paradox," remains without a mechanistic explanation. Hypothesis/Objective: Our goal is to uncover the mechanisms behind the obesity paradox in melanoma and identify therapeutic targets. We propose that adiponectin, a key adipocyte-secreted adipokine, plays a crucial role by increasing fatty acid uptake within the tumor microenvironment (TME). In obesity, adiponectin levels are reduced compared to normal weight individuals. We hypothesize that adiponectin decreases the effectiveness of BRAF/MEKi by increasing melanoma tumor fatty acid uptake in the TME. Specific Aims: In Aim 1, we will characterize the role of adiponectin within the TME of melanoma tumors in obese and non-obese mice and assess changes following treatment with BRAF/MEKi. In Aim 2, we will determine how sodium-glucose co-transporter 2 (SGLT2) inhibition alters adiponectin release, fatty acid utilization and affects BRAF/MEKi responses. Study Design: We will employ a diet-induced obesity (DIO) model in C57BL/6J mice implanted with YUMMER1.7 cells to compare adipokine release, fatty acid oxidation, adipocyte transcriptome, and immune responses between obese and non-obese mice treated with BRAF/MEKi. We will use an adiponectin knockout mouse model to explore the role of adiponectin through exogenous delivery versus its absence under similar conditions. Lastly, we will evaluate BRAF/MEKi responses in the DIO model coupled with SGLT2 inhibition, a common diabetes medication with effects on fatty acid oxidation. Impact: Our project diverges from conventional research by focusing on obesity as a favorable condition to emulate. We will elucidate how obesity alters the TME and how adiponectin affects melanoma responses to BRAF/MEKi. We anticipate discovering a unique therapeutic target that can be quickly translated into clinical practice. I firmly believe that the National Cancer Institute Early-Stage Surgeon Scientist (ESSP) program is tailor-made for my career advancement as a surgeon scientist. This program's comprehensive research training, professional development, and abundant resources will significantly accelerate my path to research independence. By participating in the ESSP, I aim to swiftly transition into a role as a principal investigator dedicated to research with direct implications for patient care and help further nurture other future surgeon scientists.