Dual Role of Tamoxifen in Enhancing STING and CEACAM1 Expression to Prime a Favorable Tumor Microenvironment for Anti‐TIM3 Immunotherapy
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 WangABSTRACT
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.