The onco-fetal immune-tolerance network: from progesterone-driven B7-H4 signaling to immunotherapeutic challenges in gynecologic cancers

The maternal-fetal interface and the tumor microenvironment (TME) of gynecologic malignancies represent two immunological settings in which semi-allogeneic or neoantigen-bearing tissues must evade immune destruction. Although these contexts have traditionally been studied in isolation, accumulating evidence reveals that pregnancy and cancer deploy remarkably convergent mechanisms of immune evasion. This review synthesizes emerging data on shared immune checkpoint molecules, metabolic immunosuppression, immune cell remodeling, and hormonal orchestration that constitute an “onco-fetal” immune tolerance network. We focus on six checkpoint axes—B7-H4, PD-L1/PD-1, HLA-G, IDO, CD47-SIRPα, and Galectin-9/TIM-3—detailing their molecular mechanisms at both the decidua and gynecologic TME. The 2024 discovery that progesterone drives B7-H4 expression through a PR-P300-BRD4 transcriptional axis—first identified in trophoblasts and breast cancer cells and likely conserved across hormone-associated malignancies including gynecologic cancers—provides a conceptual anchor for this onco-fetal framework. Notably, breast cancer serves as a mechanistic reference model in this review, while our primary focus is on ovarian, endometrial, and cervical malignancies. We further examine convergent metabolic immunosuppression (tryptophan catabolism, adenosine signaling, glucose competition, arginine depletion), paralleled remodeling of regulatory T cells, myeloid-derived suppressor cells, macrophages, and exhausted T cells, and the hormonal nexus linking these processes. The therapeutic paradox—whereby immune checkpoint inhibition is essential for cancer treatment yet contraindicated in pregnancy—underscores the translational urgency of understanding these shared pathways. We discuss B7-H4-directed antibody-drug conjugates, CD47-SIRPα blockade, IDO pathway inhibition, and bispecific antibody strategies in gynecologic oncology, alongside single-cell and spatial transcriptomic technologies reshaping our understanding of both fields. This onco-fetal perspective offers a unifying framework for developing precision immunotherapies that selectively disrupt tumor immune tolerance while preserving physiological pregnancy tolerance.