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DEHP increases PD-L1 via ERβ activation and implicates CDK4 as a mediator of immunosuppressive signaling. Palbociclib restores anti-tumor immunity and reduces immune-related adverse events triggered by anti-PD-1 therapy in mice, supporting co-targeting 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antibody for breast cancer  \nAuthors  \nShu-Wei Hu, Ming-Hsin Yeh,  \nYu-Hao He, ..., Ping-Chih Ho, Mien-Chie Hung, Wei-Chien Huang  \nCorrespondence  \nwhuang@mai[l.cmu.edu.tw](l.cmu.edu.tw)  \nIn brief  \nHu et al. show that environmental DEHP exposure promotes breast tumor initiation by impairing immune surveillance. DEHP upregulates PD-L1 via ERβ, while CDK4/6 inhibition restores anti-tumor immunity and reduces immune-related adverse events, supporting co-targeting CDK4/6 and PD-1 as a therapeutic strategy.  \n• DEHP upregulates PD-L1 via ERβ in human and mouse models  \n• Co-targeting CDK4/6 restores T cell activity and tumor immune surveillance  \n• Co-targeting CDK4/6 and PD-1 reduces immune-related adverse events  \nHu et al., 2025, Cell Reports Medicine 6, 102429  \nNovember 18, 2025 © 2025 The Authors. Published by Elsevier Inc.  \n[https://doi.org/10.1016/j.xcrm.2025.102429](https://doi.org/10.1016/j.xcrm.2025.102429)  \nll  \nll  \nOPEN ACCESS  \nArticle  \nCo-targeting CDK4/6 enhances anti-cancer activity and alleviates immune-related adverse events of anti-PD-1 antibody for breast cancer  \nShu-Wei Hu,1,2,16 Ming-Hsin Yeh,3,4,16 Yu-Hao He,2,5 Ya-Ling Wei,1,2 Fang-Ju Cheng,2,4 Yi-Lun Yeh,1,2 Thanh Kieu Huynh,1,2 Pei-Tong Liu,2 Dai-Wei Hu,1,2 Tzu-Hsuan Chang,6,7 Bo-Wei Wang,1,2 Bo-Rong Chen,1,2,8 Mei-Chun Lin,3 Der-Yen Lee,9 Yi-Hsien Hsieh,10,11 Yuan-Man Hsu,12 Chih-Hsin Tang,1,8,13,14 Ping-Chih Ho,6,7 Mien-Chie Hung,1,2,5,15 and Wei-Chien Huang1,2,5,14,15,17,*  \n1Graduate Institute of Biomedical Sciences, China Medical University, Taichung 407, Taiwan  \n2Center for Molecular Medicine, China Medical University Hospital, Taichung 407, Taiwan  \n3Department of Surgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan  \n4Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan  \n5Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung 407, Taiwan  \n6Department of Fundamental Oncology, University of Lausanne, 1015 Lausanne, Switzerland  \n7Ludwig Institute for Cancer Research, University of Lausanne, 1015 Lausanne, Switzerland  \n8School of Medicine, China Medical University, Taichung 404, Taiwan  \n9Institute of Integrated Medicine, China Medical University, Taichung 404, Taiwan  \n10Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan  \n11Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan  \n12Department of Animal Science and Biotechnology, Tunghai University, Taichung 407, Taiwan  \n13Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan  \n14Department of Medical Research, China Medical University Hsinchu Hospital, Hsinchu 302, Taiwan  \n15Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 413, Taiwan  \n16These authors contributed equally  \n17Lead contact  \n*[Correspondence:](Correspondence: whuang@mail.cmu.edu.tw)[ whuang@mail.cmu.edu.tw](Correspondence: whuang@mail.cmu.edu.tw)[ ](Correspondence: whuang@mail.cmu.edu.tw)[https://doi.org/10.1016/j.xcrm.2025.102429](https://doi.org/10.1016/j.xcrm.2025.102429)  \nSUMMARY  \nEarly-onset breast cancer (EOBC) increases annually with unclear mechanisms and shows poor therapeutic responses and survival rates. We identify environmental exposure to the common plasticizer di-2-ethylhexyl phthalate (DEHP) as a contributing factor to breast tumor initiation by impairing cancer immune surveillance. DEHP exposure upregulates the immune checkpoint molecule programmed death-ligand 1 (PD-L1) through estrogen receptor beta (ERβ) activation in human breast cancer cells and mouse models. Transcriptomic analysis reveals cyclin-dependent kinase 4 (CDK4) as a key mediator of DEHP-induced immunosuppressive signaling. The CDK4/6 inhibitor palbociclib suppresses ERβ, programmed cell death protein 1 (P","cbCaifisLtB47Q4N","https://ap.wps.com/l/cbCaifisLtB47Q4N","pdf",15774920,22,"English","# Summary\n# Introduction\n# Results and Conclusions","[{\"question\":\"What role does DEHP exposure play in early-onset breast cancer?\",\"answer\":\"DEHP exposure promotes breast tumor initiation by impairing cancer immune surveillance, contributing to immune dysregulation in early-onset breast cancer.\"},{\"question\":\"How does DEHP influence immune checkpoint signaling?\",\"answer\":\"DEHP upregulates PD-L1 through activation of estrogen receptor beta (ERβ) in human breast cancer cells and mouse models.\"},{\"question\":\"How does CDK4/6 inhibition affect anti-PD-1 therapy outcomes and safety?\",\"answer\":\"Palbociclib suppresses ERβ, PD-1, and PD-L1 expression, enhances anti-tumor responses, and reduces immune-related adverse events caused by anti-PD-1 antibody treatment in mice.\"}]","Co-targeting CDK4/6 enhances anti-cancer activity and alleviates immune-related adverse events of anti-PD-1 antibody for breast cancer | PDF",1790195448,55]