SH2B3 Promotes PD-L1-Mediated Immune Evasion in Glioblastoma via BRCC3-Dependent IGF2BP2 Stabilization.

Glioblastoma (GBM) is characterized by aggressive progression and profound immune evasion, yet the underlying mechanisms remain incompletely understood. Here, we identify the adaptor protein SH2B3 as a critical driver of immune evasion in glioblastoma and show that elevated SH2B3 expression is associated with higher glioma grade and poorer survival in public datasets and clinical data. Although SH2B3 modulation did not significantly affect GBM cell proliferation, migration, or invasion in vitro assays, it significantly altered tumorigenesis in vivo, with overexpression enhancing and knockdown suppressing tumor growth, suggesting that microenvironmental factors may contribute to the in vivo phenotype. We further show that SH2B3 promotes immune evasion at least in part by upregulating PD-L1 expression. Mechanistically, SH2B3 facilitates BRCC3-dependent removal of K63-linked polyubiquitin chains from the m⁶A reader IGF2BP2, thereby stabilizing IGF2BP2 and preventing its autophagy-lysosome-dependent degradation. The stabilized IGF2BP2 then enhances the stability and translation of m⁶A-marked PD-L1 transcripts through m⁶A-dependent transcript recognition. Collectively, our findings reveal a novel SH2B3/BRCC3/IGF2BP2 axis connecting protein deubiquitination and RNA epigenetics to PD-L1-mediated immune evasion, highlighting SH2B3 as a promising therapeutic target for glioblastoma immunotherapy.