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HEXB intercellularly manipulates tumor-associated macrophages (TAMs) to enhance GBM glycolysis, while intrinsically stabilizing HIF1α via ITGB1/ILK/YAP1 signaling and driving transcription of HEXB and glycolytic genes. Genetic ablation and pharmacologic inhibition of HEXB show substantial preclinical therapeutic effects and improve responses to immune checkpoint blockade, with 2-HG accumulation from IDH1 mutations restoring HEXB 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[https://doi.org/10.1038/s41467-024-52888-0](https://doi.org/10.1038/s41467-024-52888-0)  \nHexosaminidase B-driven cancer cellmacrophage co-dependency promotes glycolysis addiction and tumorigenesis in glioblastoma  \nReceived: 21 August 2023  \n\n| Accepted: 24 September 2024 |\n| --- |\n| |\n| Check for updates |\n\nChen Zhu1,2,3,4, Xin Chen 1,3,4, Tian-Qi Liu1,3,4, Lin Cheng2, Wen Cheng 1,3 , Peng Cheng 2,3  & An-Hua Wu 1,3   \nGlycolytic metabolic reprogramming in cancer is regulated by both cancer intrinsic variations like isocitrate dehydrogenase 1 (IDH1) status and noncancerous microenvironment components like tumor associated macrophages (TAMs). However, the detailed mechanism remains elusive. Here, we identify hexosaminidase B (HEXB) as a key regulator for glycolysis in glioblastoma (GBM). HEXB intercellularly manipulates TAMs to promote glycolysis in GBM cells, while intrinsically enhancing cancer cell glycolysis. Mechanistically, HEXB elevation augments tumor HIF1α protein stability through activating ITGB1/ILK/YAP1; Subsequently, HIF1α promotes HEXB and multiple glycolytic gene transcription in GBM cells. Genetic ablation and pharmacological inhibition of HEXB elicits substantial therapeutic effects in preclinical GBM models, while targeting HEXB doesn’t induce significant reduction in IDH1 mutant glioma and inhibiting IDH1 mutation-derived 2-hydroxyglutaric acid (2-HG) significantly restores HEXB expression in glioma cells. Our work highlights a HEXB driven TAMs-associated glycolysis-promoting network in GBM and provides clues for developing more effective therapies against it.  \nAs a cancer hallmark, deregulating cellular metabolism contributes to the initiation and progression of malignancies1. Increasing evidences suggest that cancer metabolic reprogramming is orchestrated by both intrinsic variations and the tumor microenvironment (TME)2. Although several intrinsic mechanisms including proliferation-inducing oncogenes have been uncovered in metabolic reprograming3, the interplay between cancer cells and non-tumor TME components remains elusive.  \nGlioma is the most common primary malignant tumor in adult brain. According to molecular characteristics, gliomas are basically classified into IDH1 wild type and mutant form tumors. As the most  \ncommon type of IDH1 wild type gliomas, glioblastoma (GBM) is notorious for its nature of invasive growth, which inevitably leads to recurrence and dismal prognosis even after aggressive therapeutic interventions, including extensive surgical resection, chemo- and radio-therapy4. The median survival of GBM patients is only 14.6 months, even worse than grade IV IDH1 mutant glioma5. Growing evidence suggests that GBM is accompanied by an enhanced energy production potentiality compared with grade IV IDH1 mutant tumor, as represented by the metabolic pattern towards glycolysis6. Previously, we identified that GBM featured a complex microenvironment and exhibited lower tumor purity with more abundant non-tumor cell  \n1Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China. 2Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China. 3Institute of Health Sciences, China Medical University, Shenyang, China. 4These authors contributed equally: Chen  \nZhu, Xin Chen, Tian-Qi Liu. e-mail: [cmu071207@163.com](cmu071207@163.com); [chengpeng@cmu.edu.cn](chengpeng@cmu.edu.cn); [ahwu@cmu.edu.cn](ahwu@cmu.edu.cn)  \ninfiltration, in which tumor-associated macrophages (TAMs) nearly account for 10-30%7,8, regardless of tumor subtypes9. Recently, several pioneering studies discloses that TAMs, especially M2 (anti-inflammatory) TAMs, are involved in promoting aerobic glycolysis in cancer cells10,11. The interplay between TAMs and cancer cells with enhanced glycolytic activity accounts for cancer resistance to current therapeutics. Immune cells like macrophages contribute to regulating the metabolism of glioma cells, while glioma cells","cbCaiiUFcGOgt0kz","https://ap.wps.com/l/cbCaiiUFcGOgt0kz","pdf",6255926,"English","# Background\n## Glioblastoma metabolism and microenvironment\n# Results\n## HEXB as an indicator and glycolysis regulator\n## Intrinsic HEXB-driven HIF1α signaling\n## Intercellular HEXB-TAMs glycolysis-promoting network\n## Therapeutic inhibition and IDH1 context","[{\"question\":\"What role does HEXB play in glioblastoma glycolysis?\",\"answer\":\"HEXB promotes glycolysis in glioblastoma by acting both intrinsically in cancer cells and intercellularly through tumor-associated macrophages (TAMs).\"},{\"question\":\"How does HEXB increase HIF1α activity in glioblastoma cells?\",\"answer\":\"HEXB elevation enhances HIF1α protein stability by activating an ITGB1/ILK/YAP1 pathway, leading to increased glycolytic gene transcription.\"},{\"question\":\"How does inhibiting HEXB affect therapeutic outcomes in preclinical models?\",\"answer\":\"Genetic ablation and pharmacological inhibition of HEXB produce substantial therapeutic effects in preclinical glioblastoma models and improve survival, including better response to immune checkpoint blockade.\"}]","Hexosaminidase B-driven cancer cell-macrophage co-dependency promotes glycolysis addiction and tumorigenesis in glioblastoma | PDF",1789992878,48]