Placental immunodynamics regulated by leukocytes and trophoblasts: From pregnancy to onco-fetal immunity

The placenta is a pivotal organ in pregnancy, sustaining fetal development through nutrient exchange and immunological modulation. At the maternal-fetal interface (MFI), specialized maternal immune cells within the decidua closely interact with invading trophoblasts, orchestrating a finely tuned balance between immune tolerance and activation that supports successful pregnancy outcomes. In early pregnancy, decidual immune cells are integral to trophoblast invasion and spiral artery remodeling. Subsequently, they transition to a more immunomodulatory state that promotes immune tolerance in later gestation. Perturbations in this equilibrium, including altered cell subsets or aberrant activation, are increasingly associated with adverse pregnancy complications. Meanwhile, trophoblasts express an array of immune checkpoint molecules that further modulate the immunological landscape at the MFI. This review synthesizes recent advances in immune cell dynamics at the MFI in healthy pregnancy and gestational pathologies. We also emphasize the immunoregulatory and endocrine functions of trophoblasts in orchestrating maternal-fetal tolerance. Moreover, we highlight emerging parallels in immune regulation between placental and tumor immune microenvironments, providing insights into onco-fetal immunity and suggesting broader implications of placental immunology from pregnancy to cancer immunity.