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

Undifferentiated/dedifferentiated endometrial carcinoma (UDEC) represents a rare but aggressive subtype of endometrial cancer characterized by chemoresistance. Notably, a considerable proportion of patients with UDEC who exhibit mismatch repair deficiency respond favorably to immunotherapy. Here, we identified mutations in the ribosomal protein L22 (RPL22) gene in 42% (11/26) of UDEC samples - which occurred predominantly in mismatch repair-deficient tumors. Functionally, we demonstrated that RPL22 increased the sensitivity of UDEC cells to cisplatin and lenvatinib, while promoting T-cell-mediated cytotoxicity in the presence of combined lenvatinib and pembrolizumab. RNA sequencing revealed that RPL22 overexpression in UDEC cells downregulated interferon signaling pathways, including interferon-induced protein with tetratricopeptide repeats 3 (IFIT3). Further analyses supported a potential regulatory relationship between RPL22, IFIT3, and JAK/STAT1 signaling. In xenograft experiments, RPL22 overexpression reduced tumor growth, and concurrent IFIT3 overexpression attenuated this suppressive effect at the final time point. Collectively, these findings identify RPL22 as a potential regulator of drug sensitivity and immune responses in UDEC. We propose that the RPL22-IFIT3-JAK/STAT1 axis may offer opportunities for developing personalized therapeutic strategies in UDEC.