Regional Transcriptomic Architecture of Glioblastoma Reveals NUCB2 as a Key Orchestrator of Tumour Aggression and Immune Dysfunction

Abstract

Glioblastoma (GBM) exhibits remarkable intra-tumoral heterogeneity, which contributes to therapeutic resistance and poor clinical outcomes. In this study, we employed integrative single-cell RNA sequencing analysis across two complementary public datasets encompassing diverse cellular populations from GBM centre and periphery regions to elucidate potential spatial molecular programmes driving tumour progression. Our analyses revealed substantial transcriptomic divergence between anatomically distinct tumour regions, with NUCB2 emerging as significantly upregulated in centre-residing neural progenitor cell-like (NPC-like) tumour cells. Functional characterisation demonstrated NUCB2's critical role in regulating GBM stem cell proliferation, with knockdown experiments resulting in significant reduction in tumour cell growth. Intriguingly, NUCB2 expression strongly associated with immunosuppressive molecular signatures and paradoxical immune cell infiltration patterns. Specifically, CD8+ T cells from GBM centre regions exhibited distinctive transcriptional programmes enriched for interferon response, complement activation, and inflammatory pathways, suggesting a state of functional impairment despite enhanced infiltration. Survival analyses confirmed that elevated NUCB2 expression significantly associated with poorer patient survival. Collectively, our findings establish NUCB2 as a multifaceted regulator that coordinates both intrinsic proliferative capacity and extrinsic immunomodulatory functions within the GBM microenvironment. This previously uncharacterised NUCB2-driven axis represents a promising therapeutic target, potentially enabling simultaneous targeting of tumour cell proliferation and immune evasion mechanisms in this aggressive malignancy.