Targeting Semaphorin-plexin Signaling in Glioblastoma: Implications for Tumor Invasion, Angiogenesis, and Treatment Resistance.

INTRODUCTION: Glioblastoma (GBM) is the most aggressive and malignant primary brain tumor in adults, characterized by rapid growth, diffuse invasion, marked intratumoral heterogeneity, and resistance to conventional therapies. Semaphorin-Plexin signaling, originally identified as a key regulator of axonal guidance during nervous system development, has subsequently emerged as a critical pathway involved in multiple aspects of cancer biology, including tumor proliferation, invasion, angiogenesis, immune modulation, and therapeutic resistance. METHODS: This review provides a comprehensive overview of recent findings on the role of semaphorin- plexin interactions in Glioblastoma (GBM), integrating evidence from in vitro and in vivo studies together with clinical data to highlight their biological and therapeutic significance. RESULTS: Semaphorin-plexin signaling regulates several biological processes involved in Glioblastoma (GBM) progression, including cytoskeletal remodeling, angiogenesis, and immune modulation. Distinct semaphorin receptor axes, such as Sema3A/NRP1, Sema3F/NRP2, and Sema4D/Plexin-B1, exhibit context-dependent functions and may act as either tumor suppressors or tumor promoters depending on the molecular and cellular environment. Furthermore, crosstalk between semaphorin signaling and the Vascular Endothelial Growth Factor (VEGF) pathway through neuropilins, together with the regulation of Rho family GTPases, represents a key mechanism underlying GBM angiogenesis, cell migration, and invasion. DISCUSSION: Despite its therapeutic potential, the context-dependent and bidirectional nature of semaphorin-plexin signaling poses significant challenges for clinical targeting. Resistance to therapy may arise from pathway redundancy, intratumoral heterogeneity, and dynamic interactions within the tumor microenvironment, particularly following anti-angiogenic treatment. CONCLUSION: Semaphorin-plexin signaling represents a promising yet complex therapeutic target in Glioblastoma (GBM). Future therapeutic strategies should focus on the selective modulation of this signaling pathway and its integration with combination therapies to enhance treatment efficacy and overcome therapeutic resistance.