Autophagy as a potential link between progesterone responsiveness and endometrial immune function in recurrent implantation failure.

Recurrent implantation failure (RIF) describes a clinical outcome rather than a single diagnosis or immune disorder. During progesterone-driven decidualization, changes in stromal metabolism and epithelial secretion accompany the production of signals that support uterine natural killer (uNK) cell residency. Autophagy contributes to these changes, although its role in RIF is unresolved. Genetic studies in mice and human stromal cells implicate autophagy-related proteins in progesterone responses and decidual differentiation. Some RIF tissue studies, however, report increased autophagy-associated signals. Increased flux accompanies impaired progesterone responses in some stromal models and improved decidualization in others. These contrasting findings may reflect the need to maintain autophagic activity within a suitable range for each cell compartment and cycle phase, rather than a uniform deficit. Progesterone-responsive stromal cells release interleukin 15 (IL-15) and related signals that recruit and program uNK cells. Their residency may also depend on epithelial secretion, adhesion, and matrix remodeling. In cycling human endometrium, activated uNK cells contribute to tissue quality control by clearing senescent maternal decidual cells; the embryo is not the target of this process. Single-cell and spatial studies of RIF endometrium have identified altered epithelial, stromal, and NK states. Whether progesterone resistance causes these cellular changes and, in turn, implantation failure remains unknown. This review examines the evidence for these relationships and the experiments needed to assess autophagic flux beyond static markers and uNK function beyond cell abundance. Current evidence does not support routine NK testing or autophagy-directed treatment in RIF.