While immunotherapy has revolutionized the management of advanced melanoma, many patients still do not benefit from this treatment strategy. Indeed, currently available immunotherapies are benefiting approximately 50% of stage IV melanoma patients while almost 50% of responding patients will develop disease recurrence within one year. Therefore, there is a continued need to improve our therapeutic arsenal for better managing advanced melanoma patients. We have identified a genetic profile in a significant percentage of human melanomas previously shown to be refractory to anti-PD-1 immunotherapy and we have elucidated the underlying mechanisms driving immune suppression in these melanomas. Using a melanoma model, we have determined that this genetic profile supports an immunosuppressed state and contributes to immunotherapy resistance. Based on these findings, we propose that those melanomas with this genetic profile will exhibit improved responses to immunotherapy when this immunosuppressed state is inhibited using available pharmacologic agents. To test this hypothesis, we will utilize a larger melanoma patient database to validate the importance of this genetic profile in immunotherapy resistance and examine whether this genetic profile associates with an immunosuppressed state. Further studies will be performed in melanoma models to determine if melanomas with this identified genetic profile may respond more favorably to immunotherapy if the associated immunosuppressed state can be pharmacologically reversed. Additional work utilizing human melanoma tissues will also be executed to verify that this genetic profile can predict for enhanced sensitivity to inhibiting select signaling pathways driving this immunosuppressed state. Together, this work will provide the critical foundation for executing future clinical trials that test combinatorial immunotherapy regimens tailored for melanoma patients with select genetic profiles. Ultimately, this approach is expected to broaden the melanoma population capable of benefitting from available immunotherapies.