Skin cancer is the most common form of cancer in the United States and melanoma accounts for the vast majority of skin cancer deaths. Notably, Veterans have an increased risk of developing and dying of melanoma compared to the general population. Albeit immunotherapy with immune checkpoint inhibitors (ICI) has revolutionized the treatment of melanoma, significantly improving the outcome of patients with this disease, the outcomes remain poor for Veterans with advanced melanoma. Furthermore, only 40-60% of patients experience lasting medical benefits from ICL The candidate's long-term goal is to develop new therapeutic strategies aimed at targeting this subpopulation. The significant number of refractory and relapse cases, represents an important unmet clinical need for the treatment of melanoma and proves that immune regulators such as PD-1, PD-L 1 and CTLA-4 are not the only determinants of melanoma progression and immune evasion. Notably, while inflammation has been demonstrated to influence melanoma growth and response to checkpoints inhibitors, no therapy developed to date is designed to target it This is because the tumor inflammatory pathway(s) that facilitates melanoma progression and reduces the response to immunotherapy are still poorly characterized. For this reason, the candidate's research has focused on melanoma-induced inflammation with the goal of identifying opportunities for therapeutic intervention. The hypothesis of this study is that NOD-, LRR- and pyrin domain containing 3 (NLRP3) activation reduces the efficacy of immunotherapy with checkpoint inhibitor by inducing myeloid-derived suppressor cells (MDSCs) expansion, ultimately suppressing the cos+ T and NK cells activity. The candidate further hypothesizes that NLRP3 inhibition can reverse the immunosuppressive tumor microenvironment, thereby resensitizing immunotherapy-resistant melanomas to ICI therapy. Aim1 will elucidate whether NLRP3 regulates immunosuppressive mechanism(s), including PD-L 1 expression, in melanoma cells reducing the response to ICL Aim2 will determine whether NLRP3 activation is employed by melanoma cells to suppress the host immune system. The candidate will study this by investigating the importance of NLRP3 activation on the paracrine activity of melanoma cells on immune regulatory cells like MDSCs. Aim 3 will investigate whether inhibition of NLRP3 in combination with anti-PD-1 in vivo increases the response and durability of immunotherapy using a translationally relevant model. In conclusion, these studies will establish whether NLRP3 drives resistance to ICI in melanoma, providing new insights into tumor biology, tumor immunology, and cancer therapeutics. Project Summary/Abstract