CD38 overexpression drives glioblastoma progression via L1CAM/ICAM1/JAK-STAT-Driven tumor microenvironment rewiring

BACKGROUND: Glioblastoma (GBM), a lethal primary brain malignancy, is characterized by dysregulated recruitment of tumor-associated macrophages and myeloid-derived suppressor cells, which promotes tumor growth, and enables immune evasion. Given CD38's role as a multifunctional glycoprotein in hematological malignancies where it regulates immune cell trafficking, we hypothesized that CD38 overexpression in GBM modulates the tumor immune microenvironment. METHODS: We utilized the CRISPRa system to enhance CD38 expression in mouse syngeneic GL-261 cells. A murine GBM model was generated by intracranial injection of CD38-overexpressing (CD38-OE) GL-261 cells or CD38 wild-type (WT) or (parental)GL-261 cells into C57BL/6 mice. We utilized serial brain MRIs for tumor progression and assessed overall survival using Kaplan-Meier analysis. We performed multiplex flow cytometry and cytokine assays on brain tumor tissue. Data were analyzed using one-way ANOVA and unpaired t-tests. RESULTS: Median OS was significantly reduced in CD38-OE mice (26.5 days) versus CD38-WT (35.7 days; p < 0.0001; n = 11/group). Tumor size (in vivo) in CD38-OE vs CD38-WT at day 10 (8.44 mm³ vs. 2.16 mm³; p = 0.0004) and day 17 (34.75 mm³ vs. 8.51 mm³; p = 0.0048). Compared to CD38-WT, CD38-OE tumors showed increased infiltration of glioma-associated macrophages (GAMs) (8.43-fold increase; p < 0.0001), monocytic MDSCs (12.53-fold increase; p < 0.0002), polymorphonuclear MDSCs (15.66-fold increase; p < 0.0001), and T-regs (7.22-fold increase; p < 0.0001). Cytokine profiling indicated elevated CXCL10/IP-10, TIMP-1, and ICAM-1 in CD38-OE tumors. CONCLUSIONS: CD38 overexpression in GBM drives tumor progression by amplifying immunosuppressive TME remodeling, positioning CD38 as a compelling target for further clinical investigation, supported by preliminary efficacy of daratumumab (NCT04922723) in patients with GBM.