Study shows gene changes in implantation failure, mainly affecting immune cells

A 2025 study compared changes in gene expression in the endometrium of women with or without RIF, finding many differences, with most involving immune cell populations.

Recurrent implantation failure (RIF) describes patients that have consistent implantation failure due to some underlying factor, typically defined as patients with 3 or more failed transfers.

There is still little known about what causes RIF!

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This post is a summary of a study by Tempest et al. (2025), who aimed to explore the differences in gene expression of the endometrium in 8 women with RIF compared to 8 fertile controls (without RIF or infertility). They collected endometrial biopsies during the window of implantation from both groups of women (defined as 5-9 days after the LH surge, or about 4-8 days after ovulation).

Using a technique called NanoString GeoMx spatial transcriptomics, they analyzed these biopsies to identify and compare the gene expression in two specific regions of the endometrium:

• The luminal epithelium with underlying stroma, which represents the inner surface of the uterine cavity where the embryo first makes contact and begins to implant.
• The glandular epithelium with the functionalis stroma, which represents a deeper layer that contains the glands responsible for secreting substances that support the embryo post-implantation.

They identified multiple cell types within these two regions and thousands of genes that were differentially expressed within these cell types and between women with RIF and fertile controls. This shows that there are many differences in how genes are expressed in RIF patients vs fertile controls. Notably, more than half of the differentially expressed genes were in immune cell populations (many of which were NK cells).

Among all the differentially expressed genes identified, only 57 were consistent across all regions of the endometrium. The authors highlight that by treating the endometrium as a whole, rather than as composed of distinct cell types, many of these differentially expressed genes would be overlooked.

As an example, ULBP1 was one of many genes found to be differentially expressed between women with RIF and fertile controls. This gene is involved in NK and T cell immune responses and was more active (upregulated) in women with RIF. The increased activity of ULBP1 suggests that it may affect the uterus’ ability to accept an embryo, potentially leading to implantation failure.

Other genes that were differentially expressed:

• TROPBP (involved in NK cell activation).
• ANXA7 (involved in prostaglandin E2 regulation).
• WT1 (a transcription factor shown in another study to regulate endometrial receptivity in PCOS patients).
• HCST_KLRK1 (involved in NK cell regulation).
• XRCC2 (involved in RNA repair and chromatin stability).
• JUN, JUND, and FOS (transcription factors important for uterine epithelial cell proliferation and local immune response, which are downregulated in RIF).
• MUC1, LGR5, and AGR3 (genes upregulated in luminal epithelium and involved in cellular signaling and cancer pathways).
• WNT5A and PROK1 (involved in cellular signaling and decidualization).
• ADAM15, CCDC13, and PTBP1 (genes related to wound healing, cilia formation, and RNA binding respectively, with varying expression across epithelial and stromal cells).
• TM4SF4 and PGRMC2 (related to cell adhesion and reproductive system functionality, downregulated in stromal cells of RIF patients).
• IL24 (involved in immunotolerance and angiogenic cytokine secretion during pregnancy).
• HSD3B2 (related to steroid metabolism, upregulated in certain immune cells).
• APH1A (involved in signaling pathways like Notch and WNT).

Next, the researchers used a computer-based approach to search for drugs that could either mimic or counteract the changes in gene activity observed in RIF patients. From this screening, they identified dozens of promising drug candidates, such as:

• GR-55562 (a drug that blocks serotonin receptors).
• Raloxifene (a drug that interacts with estrogen receptors in a selective way, enhancing some actions while blocking others).
• Bisoprolol (a drug that blocks β1-adrenergic receptors, which are involved in the body’s response to stress hormones).

The authors note that none of the drugs they identified target all the cell types and differentially expressed genes examined in this study, so future research will need to explore this further.

Overall, this study identifies differences in gene expression of endometrial cells in RIF patients, improving our understanding of RIF and potentially leading to targeted treatments in the future.

Reference

Tempest N, Soul J, Hill CJ, Caamaño Gutierrez E, Hapangama DK. Cell type and region-specific transcriptional changes in the endometrium of women with RIF identify potential treatment targets. Proc Natl Acad Sci U S A. 2025 Mar 18;122(11):e2421254122. doi: 10.1073/pnas.2421254122. Epub 2025 Mar 10. PMID: 40063812; PMCID: PMC11929460.

 

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About Embryoman

Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.

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