{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T03:08:09Z","timestamp":1788923289887,"version":"build-2803163510"},"reference-count":34,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"abstract":"Abstract<\/jats:title>\n \n The progression of colorectal cancer (CRC) is critically regulated by cancer\u2010associated fibroblasts (CAFs) within the tumor microenvironment (TME), yet the specific molecular mechanisms by which CAFs influence CRC remain unclear. This study reveals the mechanism by which CAFs promote CRC malignant progression and immune suppression through metabolic reprogramming. Findings indicate that lactate secreted by CAFs induces lactylation modifications of histone H3K9La and H3K18La, thereby upregulating the expression of key cholesterol synthesis enzymes DHCR7 and CYP51A1, which in turn enhances the malignant properties of CRC cells.\n In vivo<\/jats:italic>\n and\n in vitro<\/jats:italic>\n experiments confirm that inhibiting DHCR7 significantly reverses CAF\u2010mediated tumor promotion. More importantly, this study revealed that CAF\u2010induced CRC cells with elevated cholesterol metabolism deliver DHCR7 to CD8\n +<\/jats:sup>\n T cells via exosomes, thereby triggering mitochondrial dysfunction and driving the cellular senescence process. This senescence manifests as reduced IFN\u2010\u03b3 secretion capacity and enhanced senescence\u2010associated secretory phenotype (SASP). In summary, this study systematically elucidates the central role of the CAF\u2013CRC cell\u2013CD8\n +<\/jats:sup>\n T cell regulatory axis: CAF\u2010derived lactate modulates cholesterol metabolism in CRC cells via histone lactylation. Subsequently, CRC cells with enhanced cholesterol metabolism deliver DHCR7 to CD8\n +<\/jats:sup>\n T cells via exosomes, inducing mitochondrial dysfunction, which in turn leads to CD8\n +<\/jats:sup>\n T\u2010cell senescence and immunosuppression. This provides a new theoretical foundation and therapeutic rationale for metabolic\u2013immune combination strategies in CRC. \u00a9 2026 The Author(s).\n The Journal of Pathology<\/jats:italic>\n published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n <\/jats:p>","DOI":"10.1002\/path.70119","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:42:13Z","timestamp":1788921733000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CAFs<\/scp>\n \u2010mediated histone lactylation reprograms cholesterol metabolism in colorectal cancer to drive\n CD8<\/scp>\n +<\/sup>\n T cell immunosuppression"],"prefix":"10.1002","author":[{"given":"Huachi","family":"Li","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery Hubei Cancer Hospital, Tongji MedicaI College, Huazhong University of Science and Technology, Hubei Provincial Clinical Research Center for Colorectal Cancer; Wuhan Clinical Research Center for Colorectal Cancer Wuhan PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery the Fourth Hospital of Wuhan Wuhan PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Urological Surgery Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery Hubei Cancer Hospital, Tongji MedicaI College, Huazhong University of Science and Technology, Hubei Provincial Clinical Research Center for Colorectal Cancer; Wuhan Clinical Research Center for Colorectal Cancer Wuhan PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery Hubei Cancer Hospital, Tongji MedicaI College, Huazhong University of Science and Technology, Hubei Provincial Clinical Research Center for Colorectal Cancer; Wuhan Clinical Research Center for Colorectal Cancer Wuhan PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Gastrointestinal Surgery, Shenzhen Guangming District People's Hospital Shenzhen PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7646-2730","authenticated-orcid":false,"given":"Min","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery Hubei Cancer Hospital, Tongji MedicaI College, Huazhong University of Science and Technology, Hubei Provincial Clinical Research Center for Colorectal Cancer; Wuhan Clinical Research Center for Colorectal Cancer Wuhan PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","DOI":"10.3748\/wjg.v31.i5.98629","article-title":"Risk factors, prevention and screening of colorectal cancer: a rising problem","volume":"31","author":"Tsukanov VV","year":"2025","journal-title":"World J Gastroenterol"},{"key":"e_1_2_9_3_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray F","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41392-020-0116-z","article-title":"Comprehensive review of targeted therapy for colorectal cancer","volume":"5","author":"Xie YH","year":"2020","journal-title":"Signal Transduct Target Ther"},{"key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.it.2017.04.002","article-title":"Mechanisms and dynamics of T cell\u2010mediated cytotoxicity in vivo","volume":"38","author":"Halle S","year":"2017","journal-title":"Trends Immunol"},{"key":"e_1_2_9_6_1","doi-asserted-by":"crossref","DOI":"10.1155\/jimr\/4109934","article-title":"Exploring the role of cellular interactions in the colorectal cancer microenvironment","volume":"2025","author":"Tang J","year":"2025","journal-title":"J Immunol Res"},{"key":"e_1_2_9_7_1","doi-asserted-by":"crossref","first-page":"4565","DOI":"10.4251\/wjgo.v16.i12.4565","article-title":"Unraveling the role of cancer\u2010associated fibroblasts in colorectal cancer","volume":"16","author":"Cui JY","year":"2024","journal-title":"World J Gastrointest Oncol"},{"key":"e_1_2_9_8_1","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.omtn.2020.11.003","article-title":"Exosomal miR\u2010590\u20103p derived from cancer\u2010associated fibroblasts confers radioresistance in colorectal cancer","volume":"24","author":"Chen X","year":"2021","journal-title":"Mol Ther Nucleic Acids"},{"key":"e_1_2_9_9_1","doi-asserted-by":"crossref","first-page":"3506","DOI":"10.1038\/s44319-024-00180-z","article-title":"Lactate supports cell\u2010autonomous ECM production to sustain metastatic behavior in prostate cancer","volume":"25","author":"Ippolito L","year":"2024","journal-title":"EMBO Rep"},{"key":"e_1_2_9_10_1","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1158\/0008-5472.CAN-23-1448","article-title":"Spatial and single\u2010cell transcriptomics reveal a cancer\u2010associated fibroblast subset in HNSCC that restricts infiltration and antitumor activity of CD8+ T cells","volume":"84","author":"Li C","year":"2024","journal-title":"Cancer Res"},{"key":"e_1_2_9_11_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2022.887380","article-title":"Cancer associated fibroblasts \u2010 an impediment to effective anti\u2010cancer T cell immunity","volume":"13","author":"Koppensteiner L","year":"2022","journal-title":"Front Immunol"},{"key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.trecan.2020.11.008","article-title":"Targeting the mevalonate pathway in cancer","volume":"7","author":"Juarez D","year":"2021","journal-title":"Trends Cancer"},{"key":"e_1_2_9_13_1","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.it.2021.11.007","article-title":"The cholesterol pathway: impact on immunity and cancer","volume":"43","author":"King RJ","year":"2022","journal-title":"Trends Immunol"},{"key":"e_1_2_9_14_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-024-50077-7","article-title":"ATP6V0A1\u2010dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8(+) T cells","volume":"15","author":"Huang TX","year":"2024","journal-title":"Nat Commun"},{"key":"e_1_2_9_15_1","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1080\/09168451.2020.1715780","article-title":"MiR\u2010219a\u20102\u20103p suppresses cell proliferation and promotes apoptosis by targeting MDM2\/p53 in pituitary adenomas cells","volume":"84","author":"Wang Y","year":"2020","journal-title":"Biosci Biotechnol Biochem"},{"key":"e_1_2_9_16_1","doi-asserted-by":"crossref","DOI":"10.1038\/s42003-024-07041-4","article-title":"Hippo pathway in cancer cells induces NCAM1(+)\u03b1SMA(+) fibroblasts to modulate tumor microenvironment","volume":"7","author":"Thinyakul C","year":"2024","journal-title":"Commun Biol"},{"key":"e_1_2_9_17_1","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2408049121","article-title":"ACSL4\u2010mediated H3K9 and H3K27 hyperacetylation upregulates SNAIL to drive TNBC metastasis","volume":"121","author":"Sinha A","year":"2024","journal-title":"Proc Natl Acad Sci U S A"},{"key":"e_1_2_9_18_1","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1186\/s12967-025-06246-3","article-title":"Cancer\u2010associated fibroblasts promote doxorubicin resistance in triple\u2010negative breast cancer through enhancing ZFP64 histone lactylation to regulate ferroptosis","volume":"23","author":"Zhang K","year":"2025","journal-title":"J Transl Med"},{"key":"e_1_2_9_19_1","doi-asserted-by":"crossref","DOI":"10.1111\/jcmm.70789","article-title":"Dysregulated cholesterol metabolism and its impact on the tumour immune response in colorectal cancer","volume":"29","author":"Zhang C","year":"2025","journal-title":"J Cell Mol Med"},{"key":"e_1_2_9_20_1","doi-asserted-by":"crossref","DOI":"10.3390\/nu17030370","article-title":"Sleep duration, dietary inflammatory potential, and obesity in relation to colorectal cancer incidence in the multiethnic cohort","volume":"17","author":"Tembo P","year":"2025","journal-title":"Nutrients"},{"key":"e_1_2_9_21_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.tranon.2021.101043","article-title":"Influence of cholesterol on cancer progression and therapy","volume":"14","author":"Mayengbam SS","year":"2021","journal-title":"Transl Oncol"},{"key":"e_1_2_9_22_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.18699\/VJGB-22-03","article-title":"Cancer\u2010associated fibroblasts and their role in tumor progression","volume":"26","author":"Ermakov MS","year":"2022","journal-title":"Vavilov J Genet Breed"},{"key":"e_1_2_9_23_1","doi-asserted-by":"crossref","DOI":"10.48101\/ujms.v129.10710","article-title":"Interactions between cancer\u2010associated fibroblasts and T\u2010cells: functional crosstalk with targeting and biomarker potential","volume":"129","author":"Milosevic V","year":"2024","journal-title":"Ups J Med Sci"},{"key":"e_1_2_9_24_1","first-page":"384","article-title":"SP13786 inhibits the migration and invasion of lung adenocarcinoma cell A549 by Supressing Stat3\u2010EMT via CAFs exosomes","volume":"24","author":"Wang S","year":"2021","journal-title":"Zhongguo Fei Ai Za Zhi"},{"key":"e_1_2_9_25_1","doi-asserted-by":"crossref","DOI":"10.1186\/s12957-024-03482-7","article-title":"Cancer\u2010associated fibroblast\u2010derived WNT5A promotes cell proliferation, metastasis, stemness and glycolysis in gastric cancer via regulating HK2","volume":"22","author":"Xu Y","year":"2024","journal-title":"World J Surg Oncol"},{"key":"e_1_2_9_26_1","doi-asserted-by":"crossref","DOI":"10.1186\/s13578-024-01329-y","article-title":"CAFs\u2010derived lactate enhances the cancer stemness through inhibiting the MST1 ubiquitination degradation in OSC(C)","volume":"14","author":"Zhang S","year":"2024","journal-title":"Cell Biosci"},{"key":"e_1_2_9_27_1","article-title":"Enzymes in the cholesterol synthesis pathway: Interactomics in the cancer context","volume":"9","author":"Ershov P","year":"2021","journal-title":"Biomedicine"},{"key":"e_1_2_9_28_1","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.2147\/OTT.S428150","article-title":"Investigating the diagnostic and therapeutic potential of SREBF2\u2010related lipid metabolism genes in colon cancer","volume":"16","author":"Ma Y","year":"2023","journal-title":"OncoTargets Ther"},{"key":"e_1_2_9_29_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-025-57583-2","article-title":"CYP51A1 drives resistance to pH\u2010dependent cell death in pancreatic cancer","volume":"16","author":"Chen F","year":"2025","journal-title":"Nat Commun"},{"key":"e_1_2_9_30_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.tranon.2024.102261","article-title":"ENO1 promotes PDAC progression by inhibiting CD8(+) T cell infiltration through upregulating PD\u2010L1 expression via HIF\u20101\u03b1 signaling","volume":"52","author":"Aziguli T","year":"2025","journal-title":"Transl Oncol"},{"key":"e_1_2_9_31_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.tranon.2024.102081","article-title":"Transcriptional regulation of DLGAP5 by AR suppresses p53 signaling and inhibits CD8(+)T cell infiltration in triple\u2010negative breast cancer","volume":"49","author":"Pan Q","year":"2024","journal-title":"Transl Oncol"},{"key":"e_1_2_9_32_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.biopha.2023.115087","article-title":"A comprehensive review on the composition, biogenesis, purification, and multifunctional role of exosome as delivery vehicles for cancer therapy","volume":"165","author":"Li J","year":"2023","journal-title":"Biomed Pharmacother"},{"key":"e_1_2_9_33_1","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1158\/2767-9764.CRC-25-0355","article-title":"HuR\u2010regulated extracellular vesicles promote endothelial cell remodeling in pancreatic cancer","volume":"5","author":"Finan JM","year":"2025","journal-title":"Cancer Res Commun"},{"key":"e_1_2_9_34_1","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.7150\/thno.82700","article-title":"Pre\u2010metastatic niche: from revealing the molecular and cellular mechanisms to the clinical applications in breast cancer metastasis","volume":"13","author":"Li Y","year":"2023","journal-title":"Theranostics"},{"key":"e_1_2_9_35_1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/s41423-025-01371-x","article-title":"PA28\u03b3\u2010containing tumor\u2010derived exosomes promote T\u2010cell dysfunction in head and neck squamous cell carcinoma","volume":"23","author":"Wang Y","year":"2026","journal-title":"Cell Mol Immunol"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.70119","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/path.70119","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.70119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:42:23Z","timestamp":1788921743000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.70119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":34,"alternative-id":["10.1002\/path.70119"],"URL":"https:\/\/doi.org\/10.1002\/path.70119","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,8]]},"assertion":[{"value":"2026-02-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"path.70119"}}