Marvin Angelo E Aberin, Saurabh Singh, Soumya Chatterjee, Guang-Zhi Sui, Yi-Fu Wang, Ya-Ting Lu, Yu-Ling Lee, Kun-Yuan Lin, Joy Khag, Ta-Yu Liu, Shao-Han Chang, Wai-Mui Cheung, Hsiao-Chin Hong, Ren-Jun Hsu, Chen-Yang Shen, Chia-Wei Li, Weng-Lang Yang, Yao-Ming Chang, Shih-Yu Chen, Chandan Guha, Shu-Ping Wang
Despite advancements in immune checkpoint blockade (ICB) therapy, breast cancer shows limited response to anti-PD1/PD-L1 treatments, emphasizing the need for alternative ICB targets. Here, we reveal that endocrine therapeutics, specifically tamoxifen, create an immunosuppressive yet primed tumor microenvironment conducive to anti-TIM3 immunotherapy. Tamoxifen induces mitochondrial DNA damage and disrupts the RACK7/KDM5C histone demethylase complex, resulting in STING accumulation and activation of the type I interferon (IFN-I) pathway, thereby fostering an immunogenic tumor microenvironment. However, tamoxifen also elevates CEACAM1 expression via a RACK7/KDM5C axis, driving T-cell exhaustion and limiting tumor elimination. This dual effect of tamoxifen - promoting STING-mediated immunogenicity while upregulating CEACAM1 expression - shapes the tumor-immune microenvironment in both ER-positive and ER-negative tumors. Notably, combining anti-TIM3 immunotherapy with tamoxifen mitigates its immunosuppressive effects, potentially enhancing ICB efficacy. Our findings highlight the therapeutic potential of integrating anti-TIM3 immunotherapy with endocrine therapy to improve outcomes for breast cancer patients.