Identification of SAMD9 as an adaptive response gene to environmental changes and its association with overall survival and immunotherapeutic response in glioblastoma

Abstract Background Hypoxia and immune-suppressive microenvironments in glioblastoma drive transcriptional plasticity and phenotypic transition. Understanding these processes is crucial for overcoming therapy resistance and tumor relapse. This study investigates the expression pattern of sterile alpha motif domain-containing 9 (SAMD9) under these conditions, evaluates its prognostic value and spatial distribution, and explores its therapeutic implications. Methods We analyzed SAMD9 expression and its prognostic value across three independent IDH-wildtype glioblastoma cohorts and validated findings via immunohistochemistry in human glioma tissues. We mapped its spatial distribution using the IvyGAP database and leveraged integrated single-cell and spatial transcriptomic data to delineate local cellular interactions. Drug sensitivities were predicted using the oncoPredict package, and molecular docking was performed with Autodock for drug screening. Key findings regarding SAMD9 expression and its inducers were experimentally validated. Results SAMD9 was prominently expressed in an immune-suppressive subset of glioma tumor cells and was strongly associated with an interferon (IFN) signature. Elevated levels of SAMD9 correlated with reduced efficacy of anti-PD-1 treatment. Spatial mapping revealed that SAMD9 was predominantly distributed in regions of microvessel proliferation and peri-necrotic niches, where SAMD9-positive tumor cells actively interacted with vascular cells and tumor-associated macrophages (TAMs). Hypoxia and TAM co-culture significantly upregulated SAMD9, suggesting a mechanism for Bevacizumab resistance. SAMD9-high tumors exhibited TAM-dominated immune infiltration, confirmed by immune signatures profiling and histological staining. Drug prediction and molecular docking identified the multi-kinase inhibitor Dasatinib as a promising therapeutic agent for SAMD9-high IDH-wildtype glioblastoma. Conclusions SAMD9 emerges as an adaptive response gene to environmental changes, exhibiting a significant immunomodulatory function, which highlights its promise as a therapeutic target for IDH-wildtype glioblastoma.