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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>oncoPredict<\/jats:italic>\n                      package, and molecular docking was performed with Autodock for drug screening. Key findings regarding\n                      <jats:italic>SAMD9<\/jats:italic>\n                      expression and its inducers were experimentally validated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>SAMD9<\/jats:italic>\n                      was prominently expressed in an immune-suppressive subset of glioma tumor cells and was strongly associated with an interferon (IFN) signature. Elevated levels of\n                      <jats:italic>SAMD9<\/jats:italic>\n                      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\u2009tumor 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      <jats:italic>SAMD9<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12935-025-04068-3","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T16:04:38Z","timestamp":1764691478000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of SAMD9 as an adaptive response gene to environmental changes and its association with overall survival and immunotherapeutic response in glioblastoma"],"prefix":"10.1186","volume":"26","author":[{"given":"Fan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijian","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibo","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihui","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaidi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"4068_CR1","doi-asserted-by":"publisher","first-page":"299","DOI":"10.3322\/caac.21613","volume":"70","author":"AC Tan","year":"2020","unstructured":"Tan AC, Ashley DM, Lopez GY, Malinzak M, Friedman HS, Khasraw M. 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