The role of estrogen receptor signaling in suppressing the immune response to cancer.

Immune checkpoint blockade (ICB) therapies are standard of care for the treatment of many solid tumors. While some patients with cancer experience exceptional and long-term responses, intrinsic and acquired mechanisms of resistance limit the clinical efficacy of ICBs. In addition, ICBs can elicit life-threatening side effects. Alternative options that can increase ICB responses without added toxicities are needed. In this issue of the JCI, Chakraborty et al. explored the role of estrogen receptor α (ERα) in modulating ICB activity. Using transcriptomics and preclinical melanoma models, the authors show that ERα signaling in tumor-associated macrophages contributed to an immune-suppressive state within the tumor microenvironment (TME) by promoting CD8+ T cell dysfunction and exhaustion. Further, in murine melanoma models, the addition of fulvestrant, a selective estrogen receptor downregulator (SERD) approved for the treatment of breast cancer, enhanced the antitumor effects of ICB. These results provide a rationale for human trials to test the combination of antiestrogens with ICBs.