RPL22 Mutations May Shape Drug Sensitivity in Aggressive Endometrial Cancer

A ribosomal protein gene may influence how an aggressive form of endometrial cancer responds to treatment, according to a study published in the Journal of Molecular Medicine. Researchers identified mutations in the gene encoding ribosomal protein L22 (RPL22) in 42% of tumor samples—11 of 26 cases—of undifferentiated/dedifferentiated endometrial carcinoma (UDEC), a rare but aggressive subtype characterized by chemoresistance. The mutations occurred predominantly in tumors with mismatch repair deficiency, a feature already known to predict favorable responses to immunotherapy in a considerable proportion of UDEC patients.

To probe what RPL22 does in these tumors, the team conducted a series of laboratory experiments using UDEC cell lines. When RPL22 was expressed at higher levels, the cancer cells became more sensitive to two therapeutic agents: cisplatin, a conventional chemotherapy drug, and lenvatinib, a targeted kinase inhibitor. RPL22 also promoted T-cell-mediated cytotoxicity—the killing of tumor cells by immune cells—but only in the presence of combined lenvatinib and pembrolizumab, an immune checkpoint inhibitor. These findings, generated in cell culture, suggest that the gene’s status could affect how UDEC cells respond to existing combination regimens.

The molecular mechanism appeared to run through interferon signaling. RNA sequencing of UDEC cells with RPL22 overexpression showed downregulation of interferon signaling pathways, including reduced expression of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3). Further analyses supported a potential regulatory relationship linking RPL22, IFIT3, and JAK/STAT1 signaling, a pathway involved in transmitting signals from interferons and other cytokines. The authors propose that this RPL22–IFIT3–JAK/STAT1 axis may offer opportunities for developing personalized therapeutic strategies in UDEC, though this remains a hypothesis derived from the current data rather than a validated clinical approach.

The researchers also tested the effect in animal models. In xenograft experiments, in which human cancer cells are implanted into mice, RPL22 overexpression reduced tumor growth. When IFIT3 was overexpressed at the same time, this suppressive effect was attenuated at the final time point measured, supporting the idea that IFIT3 counteracts RPL22’s anti-tumor activity. The authors summarize this as evidence that RPL22 acts as a regulator of drug sensitivity and immune responses in UDEC through modulation of the JAK/STAT–IFIT3 axis.

The study’s design carries important limitations. The mutation frequency was established in a small sample of 26 tumors, reflecting the rarity of UDEC, and the functional results come from cell culture and xenograft models rather than human clinical trials. The findings therefore describe biological associations and model-based effects, not demonstrated benefits for patients. Whether RPL22 status can predict treatment response in clinical practice, or whether manipulating the IFIT3 pathway therapeutically is feasible, would require further studies in larger patient cohorts and controlled trials.

Even so, the work adds a potentially useful piece to the puzzle of an understudied cancer subtype. UDEC is aggressive and often chemoresistant, and while mismatch repair–deficient cases may respond well to immunotherapy, options for other patients remain limited. If the RPL22–IFIT3 relationship holds up in future research, it could help stratify patients or point to new drug targets. For now, the study establishes RPL22 mutation as a frequent event in this subtype—particularly among mismatch repair–deficient tumors—and provides mechanistic evidence, in preclinical models, that the gene influences drug sensitivity, immune-cell killing, and tumor growth through a defined signaling pathway.

Subject of Research: The role of RPL22 mutations and IFIT3/JAK-STAT1 signaling in undifferentiated/dedifferentiated endometrial carcinoma drug sensitivity and tumor growth

Article Title: RPL22 suppresses tumor growth in undifferentiated/dedifferentiated endometrial carcinoma through IFIT3 downregulation

Article References: Chao, A., Lin, C.-Y., Tang, W.-J., Huang, C.-Y., Wu, R.-C., Chao, A.-S., & Lai, C.-H. (2026). RPL22 suppresses tumor growth in undifferentiated/dedifferentiated endometrial carcinoma through IFIT3 downregulation. Journal of Molecular Medicine, 104(1), Article 125. https://doi.org/10.1007/s00109-026-02732-3

Image Credits: AI Generated

DOI: 10.1007/s00109-026-02732-3

Keywords: RPL22, IFIT3, endometrial carcinoma, UDEC, JAK/STAT1 signaling, mismatch repair deficiency, immunotherapy, pembrolizumab, lenvatinib, cisplatin, xenograft, tumor suppressor