ArticleJournal of experimental & clinical cancer research : CR2024
GPR65 sensing tumor-derived lactate induces HMGB1 release from TAM via the cAMP/PKA/CREB pathway to promote glioma progression.
Article in Journal of experimental & clinical cancer research : CR, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 1 of them a synthesis that pooled it.
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Who cites it
54 citing papers in PubMed, 1 synthesis or guideline pooled it, 46 citations in OpenAlex.
- From tumor microenvironment orchestrators to actionable targets: a systematic review of TAM-targeted therapies in triple-negative breast cancer.International journal of clinical oncology · 2026Pooled it
- High mobility group box 1 and its post-translational modifications: Molecular mechanisms underlying neurodegenerative disease pathogenesis.Neural regeneration research · 2026Article
- XPA lactylation is required for UV-induced DNA damage repair.Nucleic acids research · 2026Article
- The Cancer Cell Metabolic Reprogramming Remodels the Tumor Microenvironment: Molecular Mechanisms and Therapeutic Strategies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- EIF3H Modulates Glycolysis Through LDHA Stabilization in Triple-Negative Breast Cancer.Cancers · 2026Article
- Migration of immune cells in tumors and inflammation: molecular mechanisms and therapeutic targets.Signal transduction and targeted therapy · 2026Review
- Epigenetic Silencing of RFX7 Defines a Transcriptional Axis Linking Lactate Metabolism to Immune Checkpoint Therapy in Glioblastoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Dual regulation of metabolic reprogramming and protein competitive modifications: the core role and mechanism of MRPL36 in glioblastoma malignant progression.Journal of experimental & clinical cancer research : CR · 2026Article
- CircCDYL promotes glycolysis to drive the progression of nasopharyngeal carcinoma.Journal of advanced research · 2026Article
- Lactate signaling and immune suppression in tumors: mechanisms and therapeutic implications.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Precision Exercise in Type 2 Diabetes Mellitus: Targeting Signaling Networks for Lipid Homeostasis.Metabolites · 2026Review
- The PKA/MBD2 Axis Transcriptionally Represses INPP5A to Modulate PI3K/Akt Signaling and Accelerate Pituitary Tumorigenesis.CNS neuroscience & therapeutics · 2026Article
- Stiripentol directly attenuates immunosuppression of tumor-infiltrating myeloid cells to potentiate anti-PD-1 efficacy.BMC cancer · 2026Article
- Neuro-Immune Crosstalk: Molecular Mechanisms, Biological Functions, Diseases, and Therapeutic Targets.MedComm · 2026Review
- GPR65 as a Laryngeal Cancer Risk Gene Identified through Single-Cell Transcriptomics, Mendelian Randomization Analysis, and Experimental Validation.Anti-cancer agents in medicinal chemistry · 2026Article
- TMEM161B-AS1: a pivotal long non-coding RNA in the pathogenesis of glioblastoma revealed by Mendelian randomization analysis.International journal of clinical and experimental pathology · 2026Article
- Glucose metabolism in tumor-associated macrophage plasticity and cancer immunity.Frontiers in cell and developmental biology · 2026Review
- Metabolic symbiosis and competition: the dual nature of TAM-tumor cell cross-talk in tumor progression.Frontiers in oncology · 2026Review
- Metabolism of myeloid cells in brain tumors.Frontiers in immunology · 2026Review
- Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundLactate has emerged as a critical regulator within the tumor microenvironment, including glioma. However, the precise mechanisms underlying how lactate influences the communication between tumor cells and tumor-associated macrophages (TAMs), the most abundant immune cells in glioma, remain poorly understood. This study aims to elucidate the impact of tumor-derived lactate on TAMs and investigate the regulatory pathways governing TAM-mediated tumor-promotion in glioma.
methodsBioinformatic analysis was conducted using datasets from TCGA and CGGA. Single-cell RNA-seq datasets were analyzed by using UCSC Cell Browser and Single Cell Portal. Cell proliferation and mobility were evaluated through CCK8, colony formation, wound healing, and transwell assays. Western blot and immunofluorescence staining were applied to assess protein expression and cell distribution. RT-PCR and ELISA were employed to identify the potential secretory factors. Mechanistic pathways were explored by western blotting, ELISA, shRNA knockdown, and specific inhibitors and activators. The effects of pathway blockades were further assessed using subcutaneous and intracranial xenograft tumor models in vivo.
resultsElevated expressions of LDHA and MCT1 were observed in glioma and exhibited a positive correlation with M2-type TAM infiltration. Lactate derived from glioma cells induced TAMs towards M2-subtype polarization, subsequently promoting glioma cells proliferation, migration, invasion, and mesenchymal transition. GPR65, highly expressed on TAMs, sensed lactate-stimulation in the TME, fueling glioma cells malignant progression through the secretion of HMGB1. GPR65 on TAMs triggered HMGB1 release in response to lactate stimulation via the cAMP/PKA/CREB signaling pathway. Disrupting this feedback loop by GPR65-knockdown or HMGB1 inhibition mitigated glioma progression in vivo.
conclusionThese findings unveil the intricate interplay between TAMs and tumor cells mediated by lactate and HMGB1, driving tumor progression in glioma. GPR65, selectively highly expressed on TAMs in glioma, sensed lactate stimulation and fostered HMGB1 secretion via the cAMP/PKA/CREB signaling pathway. Blocking this feedback loop presents a promising therapeutic strategy for GBM.
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