The Immunoregulatory Roles of ERα in Breast Cancer: Mechanisms, Crosstalk, and Therapeutic Insights

Estrogen receptor alpha (ERα) defines the biology of estrogen receptor-positive breast cancer by regulating both tumor-intrinsic signaling and the surrounding immune microenvironment. Beyond its genomic and non-genomic actions, ERα modulates cytokine production, antigen presentation, and the activity of innate and adaptive immune cells, contributing to a low mutational burden, weak immunogenicity, and an immune-excluded tumor state. Through interactions with NF-κB, suppression of interferon pathways, and regulation of myeloid and lymphoid cell functions, ERα promotes immune tolerance and supports tumor progression. These immunoregulatory effects help explain limited responses to endocrine therapy and the poor performance of immune checkpoint inhibitors in ER-positive diseases. Emerging strategies, including next-generation selective estrogen receptor degraders and combinations with CDK4/6 inhibitors or immunotherapy, aim to overcome ERα-driven immune suppression. Understanding ERα-mediated immune regulation will be essential for developing more effective therapeutic approaches for ER-positive breast cancer.