Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.
References
Mehrian-Shai R, Reichardt JKV, Harris CC, Toren A. The Gut-Brain Axis, Paving the Way to Brain Cancer.Trends Cancer. 2019;5:200–7. [DOI] [PubMed] [PMC]
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme.Science. 2008;321:1807–12. [DOI] [PubMed] [PMC]
Bondy ML, Scheurer ME, Malmer B, Barnholtz-Sloan JS, Davis FG, Il’yasova D, et al.; Brain Tumor Epidemiology Consortium. Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium.Cancer. 2008;113:1953–68. [DOI] [PubMed] [PMC]
Trejo-Solís C, Castillo-Rodríguez RA, Serrano-García N, Silva-Adaya D, Vargas-Cruz S, Chávez-Cortéz EG, et al. Metabolic Roles of HIF1, c-Myc, and p53 in Glioma Cells.Metabolites. 2024;14:249. [DOI] [PubMed] [PMC]
Lin H, Liu C, Hu A, Zhang D, Yang H, Mao Y. Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives.J Hematol Oncol. 2024;17:31. [DOI] [PubMed] [PMC]
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer. 2012;12:252–64. [DOI] [PubMed] [PMC]
Sharma P, Allison JP. The future of immune checkpoint therapy.Science. 2015;348:56–61. [DOI] [PubMed]
Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, Archer GE, et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma.Cancer Res. 2006;66:3294–302. [DOI] [PubMed]
Jacobs JF, Idema AJ, Bol KF, Nierkens S, Grauer OM, Wesseling P, et al. Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors.Neuro Oncol. 2009;11:394–402. [DOI] [PubMed] [PMC]
El Andaloussi A, Lesniak MS. CD4+ CD25+ FoxP3+ T-cell infiltration and heme oxygenase-1 expression correlate with tumor grade in human gliomas.J Neurooncol. 2007;83:145–52. [DOI] [PubMed]
Amoozgar Z, Kloepper J, Ren J, Tay RE, Kazer SW, Kiner E, et al. Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas.Nat Commun. 2021;12:2582. [DOI] [PubMed] [PMC]
Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, et al. Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model.Cancer Immunol Res. 2016;4:124–35. [DOI] [PubMed]
Lim M, Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma.Nat Rev Clin Oncol. 2018;15:422–42. [DOI] [PubMed]
Naghavian R, Faigle W, Oldrati P, Wang J, Toussaint NC, Qiu Y, et al. Microbial peptides activate tumour-infiltrating lymphocytes in glioblastoma.Nature. 2023;617:807–17. [DOI] [PubMed] [PMC]
Ju C, Chen Y, Yang L, Huang Y, Liu J. Causal relationship between gut microbiota and glioblastoma: a two-sample Mendelian randomization study.J Cancer. 2024;15:332–42. [DOI] [PubMed] [PMC]
Wang S, Yin F, Guo Z, Li R, Sun W, Wang Y, et al. Association between gut microbiota and glioblastoma: a Mendelian randomization study.Front Genet. 2024;14:1308263. [DOI] [PubMed] [PMC]
Botticelli A, Zizzari I, Mazzuca F, Ascierto PA, Putignani L, Marchetti L, et al. Cross-talk between microbiota and immune fitness to steer and control response to anti PD-1/PDL-1 treatment.Oncotarget. 2017;8:8890–99. [DOI] [PubMed] [PMC]
Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.Science. 2018;359:104–8. [DOI] [PubMed] [PMC]
Desland FA, Hormigo A. The CNS and the Brain Tumor Microenvironment: Implications for Glioblastoma Immunotherapy.Int J Mol Sci. 2020;21:7358. [DOI] [PubMed] [PMC]
Parker A, Fonseca S, Carding SR. Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health.Gut Microbes. 2020;11:135–57. [DOI] [PubMed] [PMC]
Tanoue T, Morita S, Plichta DR, Skelly AN, Suda W, Sugiura Y, et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity.Nature. 2019;565:600–5. [DOI] [PubMed]
Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, et al. Extensive impact of non-antibiotic drugs on human gut bacteria.Nature. 2018;555:623–8. [DOI] [PubMed] [PMC]
Sanchez H, Hossain MB, Lera L, Hirsch S, Albala C, Uauy R, et al. High levels of circulating folate concentrations are associated with DNA methylation of tumor suppressor and repair genes p16, MLH1, and MGMT in elderly Chileans.Clin Epigenetics. 2017;9:74. [DOI] [PubMed] [PMC]
Zhu J, Su J. Alterations of the Gut Microbiome in Recurrent Malignant Gliomas Patients Received Bevacizumab and Temozolomide Combination Treatment and Temozolomide Monotherapy.Indian J Microbiol. 2022;62:23–31. [DOI] [PubMed] [PMC]
Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.Mol Psychiatry. 2013;18:666–73. [DOI] [PubMed]
Li T, Zhao Z, Peng M, Zhang L, Wang C, Luo F, et al. Multi-omics analysis reveals the interplay between intratumoral bacteria and glioma.mSystems. 2025;10:e0045724. [DOI] [PubMed] [PMC]
Nobels A, van Marcke C, Jordan BF, Van Hul M, Cani PD. The gut microbiome and cancer: from tumorigenesis to therapy.Nat Metab. 2025;7:895–917. [DOI] [PubMed]
Helmink BA, Khan MAW, Hermann A, Gopalakrishnan V, Wargo JA. The microbiome, cancer, and cancer therapy.Nat Med. 2019;25:377–88. [DOI] [PubMed]
Yan J, Li B, Luo C. Gut microbiota’s role in glioblastoma risk, with a focus on the mediating role of metabolites.Front Neurol. 2024;15:1386885. [DOI] [PubMed] [PMC]
Zaragoza-Ojeda M, Apatiga-Vega E, Arenas-Huertero F. Role of aryl hydrocarbon receptor in central nervous system tumors: Biological and therapeutic implications.Oncol Lett. 2021;21:460. [DOI] [PubMed] [PMC]
Mashimo T, Pichumani K, Vemireddy V, Hatanpaa KJ, Singh DK, Sirasanagandla S, et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases.Cell. 2014;159:1603–14. [DOI] [PubMed] [PMC]
Rosito M, Maqbool J, Reccagni A, Giampaoli O, Sciubba F, Antonangeli F, et al. Antibiotics treatment promotes vasculogenesis in the brain of glioma-bearing mice.Cell Death Dis. 2024;15:210. [DOI] [PubMed] [PMC]
Karpel-Massler G, Ramani D, Shu C, Halatsch ME, Westhoff MA, Bruce JN, et al. Metabolic reprogramming of glioblastoma cells by L-asparaginase sensitizes for apoptosis in vitro and in vivo.Oncotarget. 2016;7:33512–28. [DOI] [PubMed] [PMC]
Repossi R, Martín-Ramírez R, Gómez-Bernal F, Medina L, Fariña-Jerónimo H, González-Fernández R, et al. Evaluation of Zonulin Expression and Its Potential Clinical Significance in Glioblastoma.Cancers (Basel). 2024;16:356. [DOI] [PubMed] [PMC]
Pol JG, Lizarralde-Guerrero M, Checcoli A, Kroemer G. Targeted opening of the blood-brain barrier facilitates doxorubicin/anti-PD-1-based chemoimmunotherapy of glioblastoma.Oncoimmunology. 2024;13:2385124. [DOI] [PubMed] [PMC]
Jarchum I, Pamer EG. Regulation of innate and adaptive immunity by the commensal microbiota.Curr Opin Immunol. 2011;23:353–60. [DOI] [PubMed] [PMC]
Mager LF, Burkhard R, Pett N, Cooke NCA, Brown K, Ramay H, et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy.Science. 2020;369:1481–9. [DOI] [PubMed]
Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.Science. 2015;350:1079–84. [DOI] [PubMed] [PMC]
Palm NW, de Zoete MR, Flavell RA. Immune-microbiota interactions in health and disease.Clin Immunol. 2015;159:122–7. [DOI] [PubMed] [PMC]
Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.Science. 2018;359:91–7. [DOI] [PubMed]
Ferlenghi F, Castelli R, Scalvini L, Giorgio C, Corrado M, Tognolini M, et al. Drug-gut microbiota metabolic interactions: the case of UniPR1331, selective antagonist of the Eph-ephrin system, in mice.J Pharm Biomed Anal. 2020;180:113067. [DOI] [PubMed]
Fan Y, Su Q, Chen J, Wang Y, He S. Gut Microbiome Alterations Affect Glioma Development and Foxp3 Expression in Tumor Microenvironment in Mice.Front Oncol. 2022;12:836953. [DOI] [PubMed] [PMC]
Nayak L, Molinaro AM, Peters K, Clarke JL, Jordan JT, de Groot J, et al. Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma.Clin Cancer Res. 2021;27:1048–57. [DOI] [PubMed] [PMC]
Scheer KG, Ebert LM, Samuel MS, Bonder CS, Gomez GA. Bevacizumab-Induced Hypertension in Glioblastoma Patients and Its Potential as a Modulator of Treatment Response.Hypertension. 2023;80:1590–7. [DOI] [PubMed] [PMC]
de Groot J, Penas-Prado M, Alfaro-Munoz K, Hunter K, Pei BL, O’Brien B, et al. Window-of-opportunity clinical trial of pembrolizumab in patients with recurrent glioblastoma reveals predominance of immune-suppressive macrophages.Neuro Oncol. 2020;22:539–49. [DOI] [PubMed] [PMC]
Nishiyama A, Sato S, Sakaguchi H, Kotani H, Yamashita K, Ohtsubo K, et al. Pembrolizumab efficacy in a tumor mutation burden-high glioblastoma patient: A case study and implications for precision oncology.Cancer Sci. 2025;116:271–6. [DOI] [PubMed] [PMC]
Montella L, Sarno F, Altucci L, Cioffi V, Sigona L, Di Colandrea S, et al. A Root in Synapsis and the Other One in the Gut Microbiome-Brain Axis: Are the Two Poles of Ketogenic Diet Enough to Challenge Glioblastoma?Front Nutr. 2021;8:703392. [DOI] [PubMed] [PMC]
Kim Y, Varn FS, Park SH, Yoon BW, Park HR, Lee C, et al. Perspective of mesenchymal transformation in glioblastoma.Acta Neuropathol Commun. 2021;9:50. [DOI] [PubMed] [PMC]
Erta M, Quintana A, Hidalgo J. Interleukin-6, a major cytokine in the central nervous system.Int J Biol Sci. 2012;8:1254–66. [DOI] [PubMed] [PMC]
Bent EH, Millán-Barea LR, Zhuang I, Goulet DR, Fröse J, Hemann MT. Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy.Nat Commun. 2021;12:6218. [DOI] [PubMed] [PMC]
Lamano JB, Lamano JB, Li YD, DiDomenico JD, Choy W, Veliceasa D, et al. Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth.Clin Cancer Res. 2019;25:3643–57. [DOI] [PubMed] [PMC]
Keshari S, Balasubramaniam A, Myagmardoloonjin B, Herr DR, Negari IP, Huang CM. Butyric Acid from Probiotic Staphylococcus epidermidis in the Skin Microbiome Down-Regulates the Ultraviolet-Induced Pro-Inflammatory IL-6 Cytokine via Short-Chain Fatty Acid Receptor.Int J Mol Sci. 2019;20:4477. [DOI] [PubMed] [PMC]
Pham MT, Yang AJ, Kao MS, Gankhuyag U, Zayabaatar E, Jin SC, et al. Gut probiotic Lactobacillus rhamnosus attenuates PDE4B-mediated interleukin-6 induced by SARS-CoV-2 membrane glycoprotein.J Nutr Biochem. 2021;98:108821. [DOI] [PubMed] [PMC]
Qu Y, An K, Wang D, Yu H, Li J, Min Z, et al. Short-Chain Fatty Acid Aggregates Alpha-Synuclein Accumulation and Neuroinflammation via GPR43-NLRP3 Signaling Pathway in a Model Parkinson’s Disease.Mol Neurobiol. 2025;62:6612–25. [DOI] [PubMed]
Mou Y, Du Y, Zhou L, Yue J, Hu X, Liu Y, et al. Gut Microbiota Interact With the Brain Through Systemic Chronic Inflammation: Implications on Neuroinflammation, Neurodegeneration, and Aging.Front Immunol. 2022;13:796288. [DOI] [PubMed] [PMC]
Luu M, Riester Z, Baldrich A, Reichardt N, Yuille S, Busetti A, et al. Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer.Nat Commun. 2021;12:4077. [DOI] [PubMed] [PMC]
Stein-Thoeringer CK, Saini NY, Zamir E, Blumenberg V, Schubert ML, Mor U, et al. A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy.Nat Med. 2023;29:906–16. [DOI] [PubMed] [PMC]
Farina A, Villagrán-García M, Vogrig A, Joubert B. Central nervous system adverse events of immune checkpoint inhibitors.Curr Opin Neurol. 2024;37:345–52. [DOI] [PubMed]
Zhao S, Xu B, Ma W, Chen H, Jiang C, Cai J, et al. DNA Damage Repair in Brain Tumor Immunotherapy.Front Immunol. 2022;12:829268. [DOI] [PubMed] [PMC]
Mei Y, Wang X, Zhang J, Liu D, He J, Huang C, et al. Siglec-9 acts as an immune-checkpoint molecule on macrophages in glioblastoma, restricting T-cell priming and immunotherapy response.Nat Cancer. 2023;4:1273–91. [DOI] [PubMed]
McGranahan T, Therkelsen KE, Ahmad S, Nagpal S. Current State of Immunotherapy for Treatment of Glioblastoma.Curr Treat Options Oncol. 2019;20:24. [DOI] [PubMed] [PMC]
Saini S, Gadet JAMA, Freeman GJ, Chiocca EA, Mineo M. Improving IL12 immunotherapy in glioblastoma by targeting the long noncoding RNA INCR1.J Neurooncol. 2025;173:205–16. [DOI] [PubMed] [PMC]
Quist M, van Os M, van Laake LW, Bovenschen N, Crnko S. Integration of circadian rhythms and immunotherapy for enhanced precision in brain cancer treatment.EBioMedicine. 2024;109:105395. [DOI] [PubMed] [PMC]
Datta M, Chatterjee S, Perez EM, Gritsch S, Roberge S, Duquette M, et al. Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models.Proc Natl Acad Sci U S A. 2023;120:e2219199120. [DOI] [PubMed] [PMC]
Dono A, Patrizz A, McCormack RM, Putluri N, Ganesh BP, Kaur B, et al. Glioma induced alterations in fecal short-chain fatty acids and neurotransmitters.CNS Oncol. 2020;9:CNS57. [DOI] [PubMed] [PMC]
Hou X, Du H, Deng Y, Wang H, Liu J, Qiao J, et al. Gut microbiota mediated the individualized efficacy of Temozolomide via immunomodulation in glioma.J Transl Med. 2023;21:198. [DOI] [PubMed] [PMC]
Li XC, Wu BS, Jiang Y, Li J, Wang ZF, Ma C, et al. Temozolomide-Induced Changes in Gut Microbial Composition in a Mouse Model of Brain Glioma.Drug Des Devel Ther. 2021;15:1641–52. [DOI] [PubMed] [PMC]
Dees KJ, Koo H, Humphreys JF, Hakim JA, Crossman DK, Crowley MR, et al. Human gut microbial communities dictate efficacy of anti-PD-1 therapy in a humanized microbiome mouse model of glioma.Neurooncol Adv. 2021;3:vdab023. [DOI] [PubMed] [PMC]
Rossi T, Vergara D, Fanini F, Maffia M, Bravaccini S, Pirini F. Microbiota-Derived Metabolites in Tumor Progression and Metastasis.Int J Mol Sci. 2020;21:5786. [DOI] [PubMed] [PMC]
Sun J, Chen S, Zang D, Sun H, Sun Y, Chen J. Butyrate as a promising therapeutic target in cancer: From pathogenesis to clinic (Review).Int J Oncol. 2024;64:44. [DOI] [PubMed] [PMC]
Cryan JF, O’Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, et al. The Microbiota-Gut-Brain Axis.Physiol Rev. 2019;99:1877–2013. [DOI] [PubMed]
Wang J, Zhu N, Su X, Gao Y, Yang R. Gut-Microbiota-Derived Metabolites Maintain Gut and Systemic Immune Homeostasis.Cells. 2023;12:793. [DOI] [PubMed] [PMC]
Cervantes-Barragan L, Chai JN, Tianero MD, Di Luccia B, Ahern PP, Merriman J, et al. Lactobacillus reuteri induces gut intraepithelial CD4+CD8αα+ T cells.Science. 2017;357:806–10. [DOI] [PubMed] [PMC]
Li D, Li Y, Yang S, Lu J, Jin X, Wu M. Diet-gut microbiota-epigenetics in metabolic diseases: From mechanisms to therapeutics.Biomed Pharmacother. 2022;153:113290. [DOI] [PubMed]
Dempsey J, Zhang A, Cui JY. Coordinate regulation of long non-coding RNAs and protein-coding genes in germ-free mice.BMC Genomics. 2018;19:834. [DOI] [PubMed] [PMC]
Nejman D, Livyatan I, Fuks G, Gavert N, Zwang Y, Geller LT, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria.Science. 2020;368:973–80. [DOI] [PubMed] [PMC]
Zhao J, He D, Lai HM, Xu Y, Luo Y, Li T, et al. Comprehensive histological imaging of native microbiota in human glioma.J Biophotonics. 2022;15:e202100351. [DOI] [PubMed]
Drevets DA, Leenen PJ. Leukocyte-facilitated entry of intracellular pathogens into the central nervous system.Microbes Infect. 2000;2:1609–18. [DOI] [PubMed]
Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Tóth M, et al. The gut microbiota influences blood-brain barrier permeability in mice.Sci Transl Med. 2014;6:263ra158. [DOI] [PubMed] [PMC]
Da Mesquita S, Fu Z, Kipnis J. The Meningeal Lymphatic System: A New Player in Neurophysiology.Neuron. 2018;100:375–88. [DOI] [PubMed] [PMC]
Yin X, Zhang S, Lee JH, Dong H, Mourgkos G, Terwilliger G, et al. Compartmentalized ocular lymphatic system mediates eye-brain immunity.Nature. 2024;628:204–11. [DOI] [PubMed] [PMC]
Galeano Niño JL, Wu H, LaCourse KD, Kempchinsky AG, Baryiames A, Barber B, et al. Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer.Nature. 2022;611:810–7. [DOI] [PubMed] [PMC]
Akira S. TLR signaling.Curr Top Microbiol Immunol. 2006;311:1–16. [DOI] [PubMed]
Sorbara MT, Philpott DJ. Peptidoglycan: a critical activator of the mammalian immune system during infection and homeostasis.Immunol Rev. 2011;243:40–60. [DOI] [PubMed]
Clasen SJ, Bell MEW, Borbón A, Lee DH, Henseler ZM, de la Cuesta-Zuluaga J, et al. Silent recognition of flagellins from human gut commensal bacteria by Toll-like receptor 5.Sci Immunol. 2023;8:eabq7001. [DOI] [PubMed]
Larrouy-Maumus G. Lipids as Biomarkers of Cancer and Bacterial Infections.Curr Med Chem. 2019;26:1924–32. [DOI] [PubMed]
Griffin ME, Espinosa J, Becker JL, Luo JD, Carroll TS, Jha JK, et al. Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy.Science. 2021;373:1040–6. [DOI] [PubMed] [PMC]
Arabi TZ, Alabdulqader AA, Sabbah BN, Ouban A. Brain-inhabiting bacteria and neurodegenerative diseases: the “brain microbiome” theory.Front Aging Neurosci. 2023;15:1240945. [DOI] [PubMed] [PMC]
Dohlman AB, Arguijo Mendoza D, Ding S, Gao M, Dressman H, Iliev ID, et al. The cancer microbiome atlas: a pan-cancer comparative analysis to distinguish tissue-resident microbiota from contaminants.Cell Host Microbe. 2021;29:281–98.e5. [DOI] [PubMed] [PMC]
Dahl WJ, Rivero Mendoza D, Lambert JM. Diet, nutrients and the microbiome.Prog Mol Biol Transl Sci. 2020;171:237–63. [DOI] [PubMed]
Narunsky-Haziza L, Sepich-Poore GD, Livyatan I, Asraf O, Martino C, Nejman D, et al. Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions.Cell. 2022;185:3789–806.e17. [DOI] [PubMed] [PMC]
Sipos L, Banczerowski P, Juhász J, Fedorcsák I, Berényi G, Makra N, et al. Brain Tumors and Beyond: Multi-Compartment Microbiome and Mycobiome Analysis.Int J Mol Sci. 2025;26:991. [DOI] [PubMed] [PMC]