The multifunctional RNA helicase DDX39A drives glioblastoma progression by modulating WISP1 alternative splicing that induces an immunosuppressive macrophage polarization.

Glioblastoma (GB) is a highly complex ecosystem characterized by numerous interactions between tumor cells and the surrounding tumor microenvironment (TME). Splicing factors play a pivotal role in processing nascent pre-mRNA and are important in the progression of cancer, making them promising molecular targets. In this study, we demonstrate that the DEAD-box helicase 39 A (DDX39A), a RNA helicase with several important roles in RNA metabolism and cellular processes, is significantly upregulated in GB and is primarily expressed in tumor cells, leading to an immunosuppressive macrophage polarization. Through in vitro and in vivo studies, we demonstrate that reducing DDX39A expression in GB results in reduced tumor growth and invasion. Mechanistically, through RNA-seq and RIP-seq, we identified WISP1 as a critical downstream effector of DDX39A. DDX39A stabilizes WISP1 pre-mRNA through alternative splicing regulation, thereby activating the AKT signaling pathway. We further demonstrate that WISP1, when secreted by tumor cells, functions as a paracrine signaling molecule that promotes the development of immunosuppressive tumor-associated macrophages (TAMs). Additionally, we demonstrate that Fluphenazine hydrochloride binds to and inhibits DDX39A, thereby suppressing GB growth, invasion, and the immunosuppressive function of macrophages. DDX39A thus represents a potential candidate for glioma-targeted therapy.