biostudies-literatureYu JNCI NIH HHS4713-4732.e19https://www.ebi.ac.uk/biostudies/studies/S-EPMC11344674biostudies-literatureUnknown187(17)Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8⁺ T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BCellProgestogen-driven B7-H4 contributes to onco-fetal immune tolerance.PMC11344674R01 CA152470R01 CA248430R01 CA193136P30 CA046592R01 CA123088R01 CA099985R01 CA261985Freeman ZTSchon SLin XYu JVatan LGrove SZhai YSkala SWang SWei SWicha MWang WLiao PParolia AZhou JWen FZou WKryczek ISzumilo JChen LYan YXiao RChinnaiyan AMLi XRizvi SLi SHu JOkla KLin HCho KRKotarski JXu YfalseProgestogen-driven B7-H4 contributes to onco-fetal immune tolerance.Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8⁺ T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or B2024-01-01T00:00:00Z2024 Aug2026-05-29T17:17:37.901Z2026-04-08T05:26:20.089ZS-EPMC113446743896893710.1016/j.cell.2024.06.012