Reprogramming innate immunity to overcome endocrine resistance in estrogen receptor-positive breast cancer.

Abstract

Estrogen receptor-positive (ER+) breast cancer accounts for the majority of breast cancer cases worldwide, yet the long-term efficacy of endocrine therapy is limited by resistance and recurrence. While tumor-intrinsic mechanisms of endocrine resistance are well established, growing evidence highlights the contributions of innate immune cells and the tumor microenvironment (TME) in shaping therapeutic outcomes. This review synthesizes recent advances into how tumor-associated macrophages (TAMs), natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated neutrophils (TANs) collectively foster an immunosuppressive TME that undermines endocrine responsiveness. Central to this crosstalk is the STAT3 signaling pathway, which integrates inflammatory and metabolic stress signals to drive immune reprogramming, promotes tumor progression, and facilitates therapy resistance. By activating tolerogenic pathways and inhibiting anti-tumor immunity, STAT3 provides a mechanistic link between innate immune dysregulation and endocrine resistance. Preclinical studies demonstrate that STAT3 inhibition can restore tamoxifen sensitivity in resistant ER⁺ breast cancer models, highlighting its therapeutic potential. These insights reveal the immunological complexity of endocrine resistance and provide rationale for combinatorial strategies integrating endocrine therapy with immunomodulation. Future approaches that incorporate STAT3 inhibitor, immune checkpoint blockade, and biomarker-guided patient selection may transform the management of ER+ breast cancer, offering more durable and clinically meaningful outcomes by acknowledging the emerging interactions between immune dysregulation and metabolic stress in resistant ER+ breast cancer.