Novel immunological effects of estrogen receptors redefine breast cancer biology and therapy: a scoping review

This review explores the emerging immunological roles of estrogen receptors (ERs) in breast cancer. While the intrinsic tumor effects of ERs are well established, their complex interactions with the tumor immune microenvironment remain less understood. Recent clinical studies highlight the predictive value of ERα and suggest that ERα status influences responses to immunotherapy, especially in high-risk breast cancers. Ongoing clinical trials are investigating how altered ER signaling influences responses in both early and metastatic disease. Early studies have reported both immunosuppressive and immunostimulatory effects of estrogen, highlighting the intricate nature of ER-mediated immune regulation. Advances in single-cell and spatial genomics now enable a comprehensive analysis of the tumor microenvironment and reveal ER subtype-specific tumor intrinsic and extrinsic immune activities that impact both ERα-positive and ERα-negative tumors. In this timely review, we discuss novel functions of ERα and ERβ within tumor and immune cells as well as their influence on tumor progression and therapeutic response across breast cancer subtypes. We also highlight how a deeper understanding of these mechanisms can inform current clinical strategies. Finally, we consider how insights from recent and ongoing clinical trials combining immunotherapies and hormone therapies could refine future therapies to improve patient outcomes.