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

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 (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. While the strongest immune alterations appear in DEHP-exposed EOBC patients, the mechanisms extend to DEHP-associated breast cancer regardless of age. This study highlights immune dysregulation as a hallmark of DEHP-related breast carcinogenesis and supports co-targeting CDK4/6 and PD-L1 as a therapeutic strategy.