review · Immunological Reviews
Successful pregnancy requires the maternal immune system to tolerate a developing semi-identical fetus while supporting normal trophoblast cell invasion. Immune checkpoint molecules act as negative regulators of the immune response to prevent tissue damage, functioning through multiple inhibitory pathways linked to pregnancy outcomes. While early research focused on first-generation checkpoints such as PD-1 and CTLA-4, emerging attention centres on next-generation molecules including Tim-3, Tigit, Lag-3, and VISTA. These newer checkpoint molecules display specific dynamic expression profiles at the maternal-fetal interface and participate in essential processes, including decidual vascular remodelling and maternal-fetal tolerance. Disruptions in these regulatory mechanisms are linked to pathological pregnancies. Understanding these molecules offers insights for potential immunotherapy approaches to address pregnancy complications, while also clarifying how cancer treatments targeting immune checkpoints might affect pregnancy outcomes when administered to pregnant patients.
A healthy pregnancy requires a carefully balanced immune system that protects the mother without rejecting the fetus. Understanding how specialised immune checkpoint molecules prevent harmful immune attacks can explain why certain pregnancy complications arise. This knowledge helps medical researchers design targeted interventions for adverse pregnancy conditions and evaluate the safety of modern cancer immunotherapies when prescribed to pregnant patients.
The work highlights early-stage therapeutic concepts, pointing to potential immunotherapies that upregulate immune checkpoints to treat pregnancy complications, as well as guidance for managing clinical cancer therapies in pregnant patients. Target users would be biopharmaceutical developers and reproductive health researchers. Because the findings are drawn from early-stage biological review rather than clinical trials, real-world therapeutic products remain far from practical application.
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Successful pregnancy is a unique situation requires the maternal immune system to recognize and tolerate a semi-identical fetus and allow normal invasion of trophoblast cells. Although efforts have been made, the deep mechanisms of the maternal-fetal crosstalk have not yet been fully deciphered. Immune checkpoint molecules (ICMs) are a group of negative modulators of the immune response that avoid immune damage. They have been extensively studied in the fields of oncology and transplantation, while the latest evidence suggests that they are closely associated with pregnancy outcomes via multiple inhibitory mechanisms. Although studies have mostly demonstrated the regulatory role of the well-known PD-1, CTLA-4 at the maternal-fetal interface, what is unique about the newly discovered multiple ICMs remains a mystery. Here, we review the latest knowledge on ICMs, focusing on the first generation of checkpoints (PD-1, CTLA-4) and the next generation (Tim-3, Tigit, Lag-3, VISTA) highlighting their immunoregulatory roles in maternal-fetal tolerance and decidual vascular remodeling, and their involvement in pathological pregnancies. The content covers three aspects: the characteristics they possess, the dynamic expression profile of their expression at the maternal-fetal interface, and their involvement in pathological pregnancy. In immunotherapy strategies for pregnancy complications, upregulation of immune checkpoints may play a role. Meanwhile, the impact on pregnancy outcomes when using ICMs in clinical cancer treatment during pregnancy is a topic worth exploring. These may serve as a guide for future basic research and clinical applications of maternal-fetal immunity.
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DOI: 10.1111/imr.13073
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