CTNNA3 and MBP Mediate Treatment Resistance Through Tumor Microenvironment Remodeling in Recurrent Glioblastoma

Glioblastoma multiforme represents the most common primary malignant brain tumor in adults, with a 90% 2-year recurrence rate despite standard therapy of surgical resection followed by chemo- and radiotherapy. Yet, the cellular mechanisms underlying therapeutic resistance remain poorly understood. By integrating analysis of single-cell RNA sequencing results of 41 primary and 43 recurrent tumor specimens with experimental validation, we identify neuro-oligodendrocyte precursors as the predominant cellular population driving tumor recurrence through establishment of protective microenvironmental niches. We discover that CTNNA3 and MBP exhibit paradoxical roles in promoting survival in primary tumors while conferring chemoresistance in recurrent GBM, revealing that these factors determine treatment efficacy rather than directly driving relapse. Functional assays confirmed their role as mediators of extracellular matrix remodeling, establishing a mechanistic link between tumor microenvironmental remodeling and therapeutic resistance. By revealing how recurrent tumors engineer self-protective niches, our study provides a new framework for developing combination therapies that disrupt these resistance mechanisms and provides foundation for overcoming treatment failure in this universally fatal disease.