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Both tumor-intrinsic epigenetic regulation and tumor microenvironment (TME) remodeling are now understood to play pivotal roles in this resistance; however, the synergistic mechanisms and key molecular mediators underlying this interplay remain poorly defined. In this study, we demonstrated that temozolomide (TMZ) could activate the autophagy-dependent secretory pathway to promote extracellular secretion of Alpha-enolase (ENO1). Extracellular soluble ENO1 robustly enhanced GBM cell proliferation, migration, and invasion in vitro. Clinically, serum ENO1 levels were markedly elevated in GBM patients and strongly correlated with TMZ therapeutic response, suggesting its potential as a diagnostic biomarker for predicting TMZ efficacy. Mechanistically, secreted ENO1 could bind to the Toll-like receptor 4 (TLR4) receptor on GBM cells, enhancing the PI3K\/Akt pathway to promote cell invasion and proliferation. Meanwhile, ENO1\/TLR4 axis activated the downstream ERK\/SPHK1 signaling cascade, inducing phosphorylation and membrane translocation of SPHK1 at Ser225, thereby promoting the biosynthesis of sphingosine-1-phosphate (S1P), a critical sphingolipid metabolite. Notably, extracellular ENO1 and its downstream metabolite S1P synergistically polarized tumor-associated macrophages (TAMs) toward an M2-like phenotype, fostering an immunosuppressive tumor microenvironment (TME) and conferring chemoresistance. Importantly, in vivo studies confirmed that combined therapy with the SPHK1 inhibitor PF-543, the TLR4 antagonist TAK-242, and TMZ synergistically suppressed tumor growth and significantly enhanced the efficacy of TMZ. Collectively, these findings reveal that ENO1 mediates intercellular crosstalk between GBM cells and M2-TAMs via autophagy-dependent secretion, thereby driving TMZ chemoresistance and functioning as an oncogene in GBM. Targeting the ENO1\/TLR4 signaling axis reshapes the immune microenvironment and enhances the efficacy of TMZ, offering a promising therapeutic strategy and potential combinatorial targets for precision therapy in GBM.<\/jats:p>","DOI":"10.1038\/s41419-025-08313-5","type":"journal-article","created":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T12:25:05Z","timestamp":1765023905000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Autophagy-dependent secretion of ENO1 mediates chemoresistance of glioblastoma and tumor microenvironment remodeling"],"prefix":"10.1038","volume":"17","author":[{"given":"Qijun","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0034-5779","authenticated-orcid":false,"given":"Yifeng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyuan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongzhang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiakun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqi","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9570-0848","authenticated-orcid":false,"given":"Hong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4125-304X","authenticated-orcid":false,"given":"Yuntao","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,6]]},"reference":[{"key":"8313_CR1","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","volume":"23","author":"NL David","year":"2021","unstructured":"David NL, Arie P, Pieter W, Daniel JB, Ian AC, Dominique F-B, et al. 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Written informed consent was provided by all enrolled patients prior to sample collection. Animal experiments were performed using C57BL\/6 mice under protocols approved by the Animal Care and Use Committee of Nanfang Hospital, Southern Medical University, in strict accordance with institutional guidelines for animal welfare and ethical conduct of research (Approval No. IACUC-LAC-20240311-003).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"79"}}