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Here, we show that much of the melanoma protective effect likely results from estrogen signaling through the G protein-coupled estrogen receptor (GPER) on melanocytes. Selective GPER activation in primary melanocytes and melanoma cells induced long-term changes that maintained a more differentiated cell state as defined by increased expression of well-established melanocyte differentiation antigens, increased pigment production, decreased proliferative capacity, and decreased expression of the oncodriver and stem cell marker c-Myc. GPER signaling also rendered melanoma cells more vulnerable to immunotherapy. Systemically delivered GPER agonist was well tolerated, and cooperated with immune checkpoint blockade in melanoma-bearing mice to dramatically extend survival, with up to half of mice clearing their tumor. Complete responses were associated with immune memory that protected against tumor rechallenge. GPER may be a useful, pharmacologically accessible target for melanoma.<\/jats:p>","DOI":"10.7554\/elife.31770","type":"journal-article","created":{"date-parts":[[2018,1,15]],"date-time":"2018-01-15T19:00:15Z","timestamp":1516042815000},"source":"Crossref","is-referenced-by-count":141,"title":["Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade"],"prefix":"10.7554","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4949-3849","authenticated-orcid":true,"given":"Christopher A","family":"Natale","sequence":"first","affiliation":[{"name":"Perelman School of Medicine, Department of Dermatology, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyang","family":"Li","sequence":"additional","affiliation":[{"name":"Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 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