The development of new classes of drugs which target pathways required for melanoma growth and approaches to increase tumor immunogenicity (Immune Checkpoint Blockade (ICB)), have had a significant impact on outcome in this disease. However, notwithstanding the fact that “cures” are seen in ~20% of melanoma patients treated with ICBs, there remains a clear need to increase response rate. Our group has had a long-standing interest in targeting sex steroid receptors in cancer and have developed several first-in-class drugs that are now in clinical development. Not surprisingly, we were intrigued by studies which revealed that the magnitude of benefit from ICB is greater in males than females. Among the possible explanations for these findings are sex hormone dependent baseline differences in the functionality of the immune system. In support of this idea we have generated compelling data in animal models of melanoma showing that estrogens influence tumor pathobiology through actions in intratumoral immune cells. With a view to improve delivery of existing drugs, and to inform the development of the next generation of drugs for this disease, we will explore the specific mechanisms by which estrogens affect melanoma. The utility of measuring the expression of estrogen regulated genes in intratumoral immune cells as biomarkers of response to ICB therapies will also be explored. Further, preclinical studies will be performed to assess the utility of using approved anti-estrogens to increase the efficacy (patient response rates) and reduce the toxicities associated with ICB and attenuate/reverse ICB resistance. This project specifically addresses the special topic area of identification of mechanisms and biomarkers for predicting/monitoring therapeutic response. Significance: The results of our preliminary studies strongly suggest that estrogens negatively impact anti-tumor immune response which may explain the decreased efficacy of ICB in females compared to males. With the goal of developing approaches to exploit these findings in near-term clinical trials, we will assess the extent to which anti-estrogens improve the response to ICBs and evaluate the utility of using estrogen regulated genes/signatures as biomarkers to predict patient responses to ICB. Innovation: Gender differences in response to ICB have been attributed to differences in neoantigen burdens related to differences in lifestyle. We propose the additional/alternate hypothesis that estrogens, in and of themselves, impact tumor immunity in a manner that is clinically meaningful. We believe that the information gained from dissecting estrogen action in immune cells can be used to improve the delivery of existing drugs/modalities, reveal new therapeutic targets and provide new biomarkers of ICB response. Impact: Clinical trials of an ICB/ER modulator combination, the design of which will be informed by an understanding of ER action in tumor immunity, is a likely outcome of our studies.