Although immune checkpoint inhibitors (ICI) such as programmed death-1 (PD-1) blockade have made meaningful advances in the treatment of melanoma, drug resistance has limited their therapeutic efficacy as approximately 70% of patients still experience disease progression within 5 years. Therefore, understanding mechanisms of ICI therapy resistance and identification of biomarkers for predicting response to ICI treatment are unmet needs. Along with new blood vessel formation in the tumor by angiogenic factors, vascular destabilization is recognized as a hallmark of tumor growth and metastasis. Emerging evidence suggests a fundamental link between tumor vascular abnormalities and ICI therapy resistance whereby vascular destabilization impairs the immune cell infiltration to the tumor and promotes and immune evasion. Consistently, recent clinical and preclinical evidence has highlighted the importance of targeting proangiogenic factors to improve immunotherapy efficacy in cancer. Angiopoietin-2 (Ang2), which binds to the receptor tyrosine kinase Tie2, is a potent vessel-destabilizing factor and its upregulation correlates with poor prognosis and disease progression in many types of tumors. Building on our previous work on Ang2/Tie signaling in the tumor microenvironment, in this project we propose to identify Ang2/Tie signaling molecules as predictive biomarkers for immune evasion and ICI therapy resistance in melanoma. Successful completion of this project could significantly enhance the clinical management in patients with melanoma receiving ICI therapy.