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Immune checkpoint blockade (ICB) targeting PD-1/PD-L1 has transformed cancer therapy but remains ineffective in many tumor types, including endocrine-treated, relapsed estrogen receptor-positive (ER⁺) breast cancers. A team led by Dr. Shu-Ping Wang at the Institute of Biomedical Sciences (IBMS), Academia Sinica, uncovered a mechanism underlying this resistance. Chronic tamoxifen treatment reshapes the tumor microenvironment through RACK7/KDM5C-dependent epigenetic regulation, activating STING innate immune signaling and the CEACAM1/TIM3 checkpoint axis, thereby promoting T-cell exhaustion and limiting tumor elimination. Importantly, targeting CEACAM1/TIM3 counteracts tamoxifen-induced immunosuppression, revealing an actionable vulnerability and a potential strategy to enhance immunotherapy in relapsed ER⁺ breast cancer. This study was led by Dr. Wang with Dr. Marvin Aberin (TIGP-MM), Dr. Shih-Yu Chen (IBMS), and Dr. Chandan Guha (Albert Einstein College of Medicine), and supported by Academia Sinica and NSTC. This work has been published in Advanced Science (IF: 14.1) on August 17, 2026.