Hormone therapy potentiates chemoimmunotherapy by inducing SUMOylation-mediated immunogenic cell death

Abstract

Background Combining immunotherapy with endocrine therapy and/or chemotherapy promotes prognosis in patients with estrogen receptor-positive/HER2-negative (ER + HER2 − ) breast cancer; however, the unclear underlying mechanisms limit their widespread application in clinical practice. This study aimed to investigate how ER signaling regulates antitumor immunity and influences responses to chemoimmunotherapy. Methods We evaluated pathological complete response rates between ER-positive and ER-negative breast cancer patients across internal and external cohorts treated with immunotherapy and neoadjuvant chemotherapy. Mechanistic studies were conducted to explore the crosstalk between ER and immunogenic cell death (ICD) through high mobility group box 1 (HMGB1) SUMOylation. The therapeutic potential of chemoimmunotherapy regimens was assessed using immunocompetent mouse models of ER + breast cancer. Results Patients with ER − breast cancer had higher pathological complete response rates after immunotherapy and neoadjuvant chemotherapy compared with those with ER + breast cancer in both internal and external cohorts. Enhanced immune responses were observed in ER − breast cancer after chemotherapy, which was attributed to the induction of ICD via the release of HMGB1. Mechanistically, ER inhibits HMGB1 release by directly interacting with the HMG Box B domain and suppressing its SUMOylation at the K114 site, thereby suppressing the antitumor immune response. Conclusions Therapeutically, combining ER antagonist with chemotherapy potentiated the efficacy of PD-1 blockade through HMGB1 in an immunocompetent mice model. These findings provide new mechanistic insights and clinical strategies for addressing immunotherapy resistance in ER + breast cancer patients.

The authors' abstract, as published at the source. Journal for ImmunoTherapy of Cancer, 2026 · DOI ↗