ABSTRACT Immune checkpoint inhibitors (ICI) have revolutionized the care of patients with metastatic melanoma. Unfortunately, not all patients benefit from this therapy, and rational combinatorial strategies to enhance ICI efficacy in therapy non-responders are needed. We and others have shown that patients with liver metastases derive limited clinical benefit from ICI across a wide variety of disease types. In preclinical colorectal and melanoma models, we discovered that liver metastases cause immunotherapy resistance by siphoning tumor- specific T cells from systemic circulation. Within the liver, activated antigen-specific CD8+ T cells undergo apoptosis. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy reduces and metabolically refines immunosuppressive hepatic macrophages, increases hepatic T cell survival, and reduces hepatic siphoning of T cells. The central hypothesis of this proposal is that liver SBRT address ICI resistance in melanoma patients with liver metastases. We are now prospectively testing this strategy of combining liver SBRT with ipilimumab and nivolumab in melanoma patients with liver metastases. In Aim 1, we will determine whether liver SBRT combined with ipilimumab and nivolumab reverses hepatic and systemic immune dysfunction in patients enrolled on our investigator initiated clinical trial by correlating tumoral and peripheral blood immune changes with response. In Aim 2, we will determine how liver SBRT combined with ipilimumab and nivolumab reverses hepatic and systemic immune dysfunction in preclinical models of liver metastases. In Aim 3, we will determine whether liver SBRT modulates hepatic myeloid purine production and signaling to promote immune responses in metastatic melanoma. The completion of these aims as well as the associated clinical trial will establish the safety of liver SBRT with ipilimumab and nivolumab, provide preliminary efficacy measures of combination therapy, allow the development of biomarkers of response in preclinical models of liver metastases, and evaluate biomarkers of response in patients. The ultimate goal of this work is to test rationally-developed novel combination of radiotherapy and ICI in hopes of improving the care of melanoma patients with liver metastases who are resistant to immunotherapy.