Endometrial Epithelial Lactate Deficiency Drives CD8+ T-Cells Dysregulation in Unexplained Recurrent Implantation Failure

Abstract

Recurrent implantation failure (RIF), characterized by repeated failure to achieve clinical pregnancy after embryo transfer, is often associated with abnormal endometrial conditions. However, unexplained RIF is unique in that its underlying cause remains largely unknown, posing a challenge for both clinicians and patients. We performed single-cell RNA sequencing and reported that the endometria of patients with unexplained RIF exhibited increased the proliferation and activation of cytotoxic CD8⁺ T-cells, which hinder embryo implantation. Additionally, the glandular epithelium, which has the highest metabolic activity, showed abnormal glycolysis and reduced lactate production in RIF. Specifically, the endometrial expression of genes associated with glucose uptake (SLC2A1), glucose metabolism (ALDOA), lactate production (LDHA), and lactate output (SLC16A3) were lower in the patients with unexplained RIF than in the controls. Through uterine horn injection experiments in mice, we demonstrated that inhibiting lactate production in the endometrium prevents embryo implantation and that this effect could be reversed by lactate supplementation. Moreover, lactate inhibitors did not affect implantation in mice with CD8⁺ T-cells depletion. In vitro experiments also confirmed that lactate inhibition affects the proliferation and activation of CD8⁺ T-cells. We propose that the endometria of patients with unexplained RIF fail to establish proper immune balance toward the embryo, likely due to abnormal glycolysis and reduced lactate production in the glandular epithelium.

Keywords: CD8+ T‐cells; abnormal glycolysis; endometrial; glandular epithelium; recurrent implantation failure.