Co-targeting CDK4/6 enhances anti-cancer activity and alleviates immune-related adverse events of anti-PD-1 antibody for breast cancer

Sep 23, 2026

Uploaded by nayy☆

Early-onset breast cancer shows rising incidence and poor therapeutic responses, with immune dysregulation contributing to inadequate survival outcomes. The study identifies DEHP, a common plasticizer exposure, as a factor promoting breast tumor initiation by weakening immune surveillance. 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 strategies.

LanguageEnglish

CategoryHealthcare

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Pages22

Reading Time55 min

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Article Co-targeting CDK4/6 enhances anti-cancer activity and alleviates immune-related adverse events of anti-PD-1 antibody for breast cancer Authors Shu-Wei Hu, Ming-Hsin Yeh, Yu-Hao He, ..., Ping-Chih Ho, Mien-Chie Hung, Wei-Chien Huang Correspondence whuang@mai[l.cmu.edu.tw](l.cmu.edu.tw) In brief Hu 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. • DEHP upregulates PD-L1 via ERβ in human and mouse models • Co-targeting CDK4/6 restores T cell activity and tumor immune surveillance • Co-targeting CDK4/6 and PD-1 reduces immune-related adverse events Hu et al., 2025, Cell Reports Medicine 6, 102429 November 18, 2025 © 2025 The Authors. Published by Elsevier Inc. [https://doi.org/10.1016/j.xcrm.2025.102429](https://doi.org/10.1016/j.xcrm.2025.102429) ll ll OPEN ACCESS Article Co-targeting CDK4/6 enhances anti-cancer activity and alleviates immune-related adverse events of anti-PD-1 antibody for breast cancer Shu-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,* 1Graduate Institute of Biomedical Sciences, China Medical University, Taichung 407, Taiwan 2Center for Molecular Medicine, China Medical University Hospital, Taichung 407, Taiwan 3Department of Surgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan 4Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan 5Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung 407, Taiwan 6Department of Fundamental Oncology, University of Lausanne, 1015 Lausanne, Switzerland 7Ludwig Institute for Cancer Research, University of Lausanne, 1015 Lausanne, Switzerland 8School of Medicine, China Medical University, Taichung 404, Taiwan 9Institute of Integrated Medicine, China Medical University, Taichung 404, Taiwan 10Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan 11Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan 12Department of Animal Science and Biotechnology, Tunghai University, Taichung 407, Taiwan 13Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan 14Department of Medical Research, China Medical University Hsinchu Hospital, Hsinchu 302, Taiwan 15Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 413, Taiwan 16These authors contributed equally 17Lead contact *[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) SUMMARY Early-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

FAQs

What role does DEHP exposure play in early-onset breast cancer?

DEHP exposure promotes breast tumor initiation by impairing cancer immune surveillance, contributing to immune dysregulation in early-onset breast cancer.

How does DEHP influence immune checkpoint signaling?

DEHP upregulates PD-L1 through activation of estrogen receptor beta (ERβ) in human breast cancer cells and mouse models.

How does CDK4/6 inhibition affect anti-PD-1 therapy outcomes and safety?

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.

Sep 23, 2026

Uploaded by nayy☆