Abstract / Summary
Abstract Glioblastoma (GBM) microenvironment is profoundly immunosuppressive; however, whether hnRNPC mediates immune escape in GBM and the specific mechanism involved remain unclear. Therefore, this study investigated the role of hnRNPC in the immune evasion process of GBM and the related upstream and downstream regulatory pathways. GBM transcriptomic data from TCGA, GTEx, and scRNA-seq datasets were collected to assess hnRNPC expression and immune signatures in GBM, and the findings were validated in clinical specimens. Across patient samples and preclinical models, hnRNPC was upregulated in GBM, and its expression inversely correlated with CD8⁺ T cell infiltration. Functional assays revealed that hnRNPC promotes tumor progression, reduces CD8⁺ T cell infiltration, and increases PD-L1 membrane expression. Mechanistically, hnRNPC protein stabilizes PSD4 mRNA through recognition of the m6A modification, thereby activating the ARF6–AMAP1 pathway, which enhances PD-L1 membrane presentation and impairs CD8 + T cell cytotoxicity. Upstream, BTRC mediates K48-linked ubiquitination of hnRNPC, thereby promoting its proteasomal degradation. Therapeutically, targeting hnRNPC enhanced anti–PD-1 immunotherapy efficacy. In conclusion, hnRNPC is regulated by BTRC-mediated ubiquitination and promotes GBM immune evasion by stabilizing PSD4 and driving the ARF6/AMAP1/PD-L1 axis. This pathway represents a promising target for enhancing GBM immunotherapy.