Targeting the IRE1α-XBP1 signaling axis impairs tumor growth and promotes myogenic differentiation in rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma arising from mesenchymal progenitors with skeletal muscle features. The unfolded protein response (UPR) maintains proteostasis during endoplasmic reticulum stress, with the IRE1α-XBP1 axis representing a key signaling branch. Here, we demonstrate that components of this pathway are significantly upregulated in RMS cell lines and primary tumors. Genetic or pharmacological inhibition of IRE1α or spliced XBP1 (sXBP1) suppresses cell proliferation, promotes terminal myogenic differentiation, and enhances vincristine-induced cytotoxicity in RMS cells. Silencing of sXBP1 further reduces the cancer stem-like cell population and impairs migration and invasion. Mechanistically, IRE1α-XBP1 signaling promotes RMS progression through sXBP1-dependent upregulation of BMPR1A and subsequent activation of BMP-SMAD1 signaling. Consistently, inducible knockdown of sXBP1 or pharmacological inhibition of IRE1α endonuclease activity significantly attenuates xenograft RMS growth. Collectively, these findings identify the IRE1α-XBP1 axis as a critical regulator of RMS growth, differentiation, and chemosensitivity, and support its therapeutic targeting in RMS. The IRE1α-XBP1 arm of the UPR is upregulated in rhabdomyosarcoma and drives tumor growth, stemness, migration, and invasion, while its inhibition promotes differentiation and enhances vincristine efficacy. We are grateful to Dr. Peter J Houghton of The University of Texas Health Science Center at San Antonio, Texas, for providing RH36 and RH41 cell lines. We thank the technical support from the Cancer Prevention and Research Institute of Texas (CPRIT R... [1010 chars]