{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T18:23:41Z","timestamp":1787250221818,"version":"build-2736575974"},"reference-count":33,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Talent Development Special Support Program of Daqing City","award":["DQXY202408"],"award-info":[{"award-number":["DQXY202408"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Exercise-related genes (ERGs) have emerged as potential modulators of tumor biology, yet their systematic characterization in hepatocellular carcinoma (HCC) remains incomplete. Here we integrated 320 ERGs from MSigDB with TCGA-HCC cohort to construct an interaction-perturbation network, identifying two distinct subtypes with divergent prognostic outcomes. Cluster1 (44.4% of patients) exhibited significantly higher network perturbation scores, activated proliferation and epithelial-mesenchymal transition pathways, and elevated immune checkpoint gene expression, collectively contributing to poorer survival. This subtype also demonstrated enhanced immune evasion potential and lower predicted immunotherapy response rates. Conversely, Cluster2 (55.6%) was characterized by metabolic pathway enrichment, increased\n                    <jats:italic>CTNNB1<\/jats:italic>\n                    mutations, higher tumor mutational burden, and more favorable immunotherapy prediction. Notably, integrated analysis of intratumoral microbiota revealed that\n                    <jats:italic>Streptomyces<\/jats:italic>\n                    abundance was significantly associated with immune exclusion features and negatively correlated with both exercise-related and lactate metabolic pathways. Mediation analysis further suggested that elevated lactate metabolism was statistically associated with adaptive microbial changes, which in turn showed directional associations with exercise-related pathway activity and clinical outcomes. Using\n                    <jats:italic>Streptomyces<\/jats:italic>\n                    -associated host genes, we developed an 8-gene prognostic signature that effectively stratified patient outcomes and predicted immunotherapy response across multiple independent cohorts. Our findings delineate exercise-related molecular subtypes with distinct immune-microbiota-metabolic crosstalk and provide a clinically applicable signature for risk stratification in HCC.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0356502","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T17:26:46Z","timestamp":1787246806000},"page":"e0356502","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Streptomyces-linked exercise gene networks orchestrate immune exclusion and determine immunotherapy response in hepatocellular carcinoma"],"prefix":"10.1371","volume":"21","author":[{"given":"Xiaoting","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dapeng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0442-1409","authenticated-orcid":true,"given":"Yingwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuopeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yudiao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"issue":"3","key":"pone.0356502.ref001","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"H Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"issue":"2","key":"pone.0356502.ref002","doi-asserted-by":"crossref","DOI":"10.1148\/radiol.232875","article-title":"Interventional oncology meets immuno-oncology: combination therapies for hepatocellular carcinoma","volume":"313","author":"R Bitar","year":"2024","journal-title":"Radiology"},{"issue":"1","key":"pone.0356502.ref003","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S1470-2045(21)00604-5","article-title":"Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial","volume":"23","author":"T Yau","year":"2022","journal-title":"Lancet Oncol"},{"issue":"3","key":"pone.0356502.ref004","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.cnc.2022.04.004","article-title":"Hepatocellular Carcinoma","volume":"34","author":"H Gilles","year":"2022","journal-title":"Crit Care Nurs Clin North Am"},{"issue":"7","key":"pone.0356502.ref005","article-title":"Intratumoural microbiome can predict the prognosis of hepatocellular carcinoma after surgery","volume":"13","author":"L Sun","year":"2023","journal-title":"Clin Transl Med"},{"issue":"8","key":"pone.0356502.ref006","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1158\/2159-8290.CD-24-1259","article-title":"Intrahepatic microbial heterogeneity in multifocal hepatocellular carcinoma and its association with host genomic and transcriptomic alterations","volume":"15","author":"Y Lu","year":"2025","journal-title":"Cancer Discov"},{"issue":"7938","key":"pone.0356502.ref007","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41586-022-05400-x","article-title":"Liver tumour immune microenvironment subtypes and neutrophil heterogeneity","volume":"612","author":"R Xue","year":"2022","journal-title":"Nature"},{"issue":"1","key":"pone.0356502.ref008","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/s41420-025-02642-2","article-title":"RBM17 promotes hepatocellular carcinoma progression by regulating lipid metabolism and immune microenvironment: implications for therapeutic targeting","volume":"11","author":"Z Wang","year":"2025","journal-title":"Cell Death Discov"},{"key":"pone.0356502.ref009","doi-asserted-by":"crossref","first-page":"1606711","DOI":"10.3389\/fimmu.2025.1606711","article-title":"Exercise-related immune gene signature for hepatocellular carcinoma: machine learning and multi-omics analysis","volume":"16","author":"C Pu","year":"2025","journal-title":"Front Immunol"},{"key":"pone.0356502.ref010","doi-asserted-by":"crossref","first-page":"747933","DOI":"10.3389\/fmolb.2021.747933","article-title":"Methylation and Expression of the Exercise-Related TLR1 Gene Is Associated With Low Grade Glioma Prognosis and Outcome","volume":"8","author":"L Lu","year":"2021","journal-title":"Front Mol Biosci"},{"key":"pone.0356502.ref011","doi-asserted-by":"crossref","first-page":"1476076","DOI":"10.3389\/fphar.2024.1476076","article-title":"Targeting exercise-related genes and placental growth factor for therapeutic development in head and neck squamous cell carcinoma","volume":"15","author":"Q Shi","year":"2024","journal-title":"Front Pharmacol"},{"issue":"1","key":"pone.0356502.ref012","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/s41598-022-26700-2","article-title":"Effects of the exercise-inducible myokine irisin on proliferation and malignant properties of ovarian cancer cells through the HIF-1 \u03b1 signaling pathway","volume":"13","author":"M Alizadeh Zarei","year":"2023","journal-title":"Sci Rep"},{"key":"pone.0356502.ref013","doi-asserted-by":"crossref","first-page":"105708","DOI":"10.1016\/j.ebiom.2025.105708","article-title":"The metabolic dialogue between intratumoural microbes and cancer: implications for immunotherapy","volume":"115","author":"Y Situ","year":"2025","journal-title":"EBioMedicine"},{"issue":"9","key":"pone.0356502.ref014","doi-asserted-by":"crossref","first-page":"102306","DOI":"10.1016\/j.xcrm.2025.102306","article-title":"Identification and validation of intratumoral microbiome associated with sensitization to immune checkpoint inhibitors","volume":"6","author":"J Chen","year":"2025","journal-title":"Cell Rep Med"},{"issue":"8","key":"pone.0356502.ref015","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1158\/0008-5472.CAN-25-0346","article-title":"Intratumoral Lactobacillus johnsonii Enhances Sensitivity to PD-1 Blockade by Inducing CD8+ T-cell Expansion in Hepatocellular Carcinoma","volume":"86","author":"Q Liu","year":"2026","journal-title":"Cancer Res"},{"issue":"4","key":"pone.0356502.ref016","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2019.07.008","article-title":"Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes","volume":"178","author":"E Riquelme","year":"2019","journal-title":"Cell"},{"issue":"1","key":"pone.0356502.ref017","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1007\/s12672-026-04613-0","article-title":"Lactate metabolism-related interaction perturbation network enables robust stratification of hepatocellular carcinoma","volume":"17","author":"S Li","year":"2026","journal-title":"Discov Oncol"},{"key":"pone.0356502.ref018","doi-asserted-by":"crossref","first-page":"105966","DOI":"10.1016\/j.phrs.2021.105966","article-title":"Influence of gut and intratumoral microbiota on the immune microenvironment and anti-cancer therapy","volume":"174","author":"Y Chen","year":"2021","journal-title":"Pharmacol Res"},{"issue":"1","key":"pone.0356502.ref019","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41392-024-02082-x","article-title":"Lactate and lactylation in cancer","volume":"10","author":"J Chen","year":"2025","journal-title":"Signal Transduct Target Ther"},{"key":"pone.0356502.ref020","first-page":"0793","article-title":"Lactylation in Tumor Immune Escape and Immunotherapy: Multifaceted Functions and Therapeutic Strategies","volume":"8","author":"Q Li","year":"2025","journal-title":"Research (Wash D C)"},{"issue":"9","key":"pone.0356502.ref021","article-title":"Tumor-associated Schwann cell remodeling under metabolic stress via lactate sensing orchestrates pancreatic ductal adenocarcinoma development","volume":"37","author":"Y Liu","year":"2025","journal-title":"Cell Metab"},{"issue":"4","key":"pone.0356502.ref022","doi-asserted-by":"crossref","DOI":"10.1093\/bib\/bbaa268","article-title":"Sample-specific perturbation of gene interactions identifies breast cancer subtypes","volume":"22","author":"Y Chen","year":"2021","journal-title":"Brief Bioinform"},{"key":"pone.0356502.ref023","article-title":"136 ultrahigh tumor mutational burden (TMB) is associated with improved survival outcomes in patients (Pts) treated with immune checkpoint inhibitors (ICIs)","volume":"13","author":"DB Johnson","year":"2025","journal-title":"Journal for ImmunoTherapy of Cancer"},{"issue":"1","key":"pone.0356502.ref024","doi-asserted-by":"crossref","first-page":"200933","DOI":"10.1016\/j.omton.2025.200933","article-title":"Metabolites and metabolic pathway reactions links to sensitization of immunotherapy in pan-cancer","volume":"33","author":"S Yu","year":"2025","journal-title":"Mol Ther Oncol"},{"key":"pone.0356502.ref025","doi-asserted-by":"crossref","first-page":"853","DOI":"10.3389\/fonc.2020.00853","article-title":"An Integrative Analysis Reveals the Underlying Association Between CTNNB1 Mutation and Immunotherapy in Hepatocellular Carcinoma","volume":"10","author":"Z Mo","year":"2020","journal-title":"Front Oncol"},{"issue":"1","key":"pone.0356502.ref026","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s13045-025-01732-z","article-title":"The role of neoantigens and tumor mutational burden in cancer immunotherapy: advances, mechanisms, and perspectives","volume":"18","author":"S Sun","year":"2025","journal-title":"J Hematol Oncol"},{"key":"pone.0356502.ref027","first-page":"5350232","article-title":"Prognostic and Immunological Significance of CXCR2 in Ovarian Cancer: A Promising Target for Survival Outcome and Immunotherapeutic Response Assessment","volume":"2021","author":"H Ji","year":"2021","journal-title":"Dis Markers"},{"issue":"3","key":"pone.0356502.ref028","article-title":"Intratumoral bacterium Enterocloster bolteae promotes hepatocellular carcinoma progression by directly binding tumor cells","volume":"34","author":"X Ren","year":"2026","journal-title":"Cell Host Microbe"},{"issue":"1","key":"pone.0356502.ref029","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/s41392-022-01159-9","article-title":"Intratumoral bacteria interact with metabolites and genetic alterations in hepatocellular carcinoma","volume":"7","author":"C Xue","year":"2022","journal-title":"Signal Transduct Target Ther"},{"issue":"8","key":"pone.0356502.ref030","doi-asserted-by":"crossref","first-page":"9971","DOI":"10.1007\/s00210-025-04001-5","article-title":"Unlocking the microbial treasure trove: advances in Streptomyces derived secondary metabolites in the battle against cancer","volume":"398","author":"A Mukherjee","year":"2025","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"pone.0356502.ref031","doi-asserted-by":"crossref","first-page":"968053","DOI":"10.3389\/fmicb.2022.968053","article-title":"Streptomyces: The biofactory of secondary metabolites","volume":"13","author":"K Alam","year":"2022","journal-title":"Front Microbiol"},{"issue":"1","key":"pone.0356502.ref032","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s13046-024-03042-7","article-title":"Pan-cancer analysis implicates novel insights of lactate metabolism into immunotherapy response prediction and survival prognostication","volume":"43","author":"D Chen","year":"2024","journal-title":"J Exp Clin Cancer Res"},{"key":"pone.0356502.ref033","doi-asserted-by":"crossref","first-page":"217077","DOI":"10.1016\/j.canlet.2024.217077","article-title":"Pan-cancer atlas of tumor-resident microbiome, immunity and prognosis","volume":"598","author":"D Sheng","year":"2024","journal-title":"Cancer Lett"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0356502","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T17:26:50Z","timestamp":1787246810000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0356502"}},"subtitle":[],"editor":[{"given":"Zhanzhan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":33,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0356502","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]}}}