{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:24Z","timestamp":1792787304339,"version":"4.5.0"},"reference-count":54,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2025,6,22]],"date-time":"2025-06-22T00:00:00Z","timestamp":1750550400000},"content-version":"unspecified","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"crossref","award":["No. 81902927"],"award-info":[{"award-number":["No. 81902927"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Nature Science Foundation of Chongqing","award":["CSTB2023NSCQ-ZDJ0020"],"award-info":[{"award-number":["CSTB2023NSCQ-ZDJ0020"]}]},{"name":"Nature Science Foundation of Chongqing","award":["CSTB2022NSCQ-MSX0220"],"award-info":[{"award-number":["CSTB2022NSCQ-MSX0220"]}]},{"name":"Nature Science Foundation of Chengdu","award":["Q21055"],"award-info":[{"award-number":["Q21055"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,6,2]]},"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The treatment of colorectal cancer liver metastasis (CRLM), a leading cause of mortality in patients with colorectal cancer, is complicated by type 2 diabetes (T2D). This study aimed to investigate the CRLM immune microenvironment in the context of T2D and identify potential therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A hyperglycemic CRLM mouse model was established. Seven single-cell RNA sequencing datasets were analyzed, including three peripheral blood mononuclear cells (PBMCs) datasets (from healthy donors and T2D patients) and four datasets with 20 CRLM samples and matching PBMCs datasets, to explore the immune characteristics and remodeling of the tumor microenvironment in CRLM with concurrent T2D.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells exhibited dysfunction and exhaustion in liver metastasis from patients with CRLM and T2D; the proportions of various CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell subpopulations were also altered, and the number of myeloid cells and their function was increased. Myeloid cells in CRLM from patients with T2D exhibited high expression levels of CCL3, which recruited peripheral blood monocytes expressing high levels of CCR1, leading to an accumulation of myeloid cells and an immunosuppressive tumor microenvironment. Recruited cells exhibited enhanced T cell communication abilities, indicating an augmented immunosuppressive capacity. In addition, CCR1 expression in peripheral blood monocytes from patients with CRLM was closely correlated with the immunosuppressive tumor microenvironment, suggesting that CCR1 expression levels may predict immune cell phenotype and prognosis in patients with CRLM and T2D.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study revealed complex changes in the tumor microenvironment of patients with CRLM and T2D. In particular, a novel mechanism was identified by which hyperglycemia regulates immunosuppression: the CCL3\u2013CCR1 signaling axis. This finding offers a novel potential therapeutic target for patients with CRLM and T2D and provides an important theoretical basis for the future prediction of the prognosis of these patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-011310","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T03:15:12Z","timestamp":1750648512000},"page":"e011310","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Hyperglycemia induces an immunosuppressive microenvironment in colorectal cancer liver metastases by recruiting peripheral blood monocytes through the CCL3-CCR1 axis"],"prefix":"10.1136","volume":"13","author":[{"given":"Han","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, School of Medicine, Chongqing University Cancer Hospital, Chongqing University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuesong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Fan","sequence":"additional","affiliation":[{"name":"Endocrinology\/Osteoporosis, West China School of Public Health and West China Forth Hospital, Sichuan University, Chengdu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lintao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hematology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongtao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, School of Medicine, Chongqing University Cancer Hospital, Chongqing University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4402-5472","authenticated-orcid":false,"given":"Jianjun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houjie","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9561-6149","authenticated-orcid":false,"given":"Shuo","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,6,22]]},"reference":[{"key":"2026052722353761000_13.6.e011310.1","unstructured":"Magliano DJ , Boyko EJ . IDF diabetes atlas 10th edition scientific committee. In: IDF diabetes atlas. 10th edn. Brussels: International Diabetes Federation, 2021."},{"key":"2026052722353761000_13.6.e011310.2","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2023.43333","article-title":"Type 2 Diabetes and Colorectal Cancer Risk","volume":"6","author":"Lawler","year":"2023","journal-title":"JAMA Netw Open"},{"key":"2026052722353761000_13.6.e011310.3","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.ctrv.2018.08.004","article-title":"Challenges and perspectives in the treatment of diabetes associated breast cancer","volume":"70","author":"Samuel","year":"2018","journal-title":"Cancer Treat Rev"},{"key":"2026052722353761000_13.6.e011310.4","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2020.7653"},{"key":"2026052722353761000_13.6.e011310.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-023-00841-9"},{"key":"2026052722353761000_13.6.e011310.6","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.18632\/oncotarget.27674","article-title":"Diabetes mellitus is associated with liver metastasis of colorectal cancer through production of biglycan-rich cancer stroma","volume":"11","author":"Fujiwara-Tani","year":"2020","journal-title":"Oncotarget"},{"key":"2026052722353761000_13.6.e011310.7","article-title":"Prognostic Impact of Type 2 Diabetes in Metastatic Colorectal Cancer","volume":"15","author":"Miranda Baleiras","year":"2023","journal-title":"Cureus"},{"key":"2026052722353761000_13.6.e011310.8","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1002\/1878-0261.13122","article-title":"Metastatic colorectal cancer and type 2 diabetes: prognostic and genetic interactions","volume":"16","author":"Ottaiano","year":"2022","journal-title":"Mol Oncol"},{"key":"2026052722353761000_13.6.e011310.9","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.9783"},{"key":"2026052722353761000_13.6.e011310.10","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.canep.2017.04.003","article-title":"Stage IV colorectal cancer primary site and patterns of distant metastasis","volume":"48","author":"Robinson","year":"2017","journal-title":"Cancer Epidemiol"},{"key":"2026052722353761000_13.6.e011310.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2022.08.002"},{"key":"2026052722353761000_13.6.e011310.12","doi-asserted-by":"crossref","first-page":"2511","DOI":"10.1016\/j.cmet.2024.10.004","article-title":"Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes","volume":"36","author":"Gray","year":"2024","journal-title":"Cell Metab"},{"key":"2026052722353761000_13.6.e011310.13","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1038\/s41423-022-00894-x","article-title":"Glucose metabolism controls human \u03b3\u03b4 T-cell-mediated tumor immunosurveillance in diabetes","volume":"19","author":"Mu","year":"2022","journal-title":"Cell Mol Immunol"},{"key":"2026052722353761000_13.6.e011310.14","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-3116"},{"key":"2026052722353761000_13.6.e011310.15","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1053\/j.gastro.2022.11.029","article-title":"Integrated Multi-Omics Landscape of Liver Metastases","volume":"164","author":"Yang","year":"2023","journal-title":"Gastroenterology"},{"key":"2026052722353761000_13.6.e011310.16","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-2041"},{"key":"2026052722353761000_13.6.e011310.17","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.adf5464","article-title":"Data from: Single-cell and spatial transcriptome analysis reveals the cellular heterogeneity of liver metastatic colorectal cancer","volume":"9","author":"Wang","year":"2023","journal-title":"Sci Adv"},{"key":"2026052722353761000_13.6.e011310.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1131-x"},{"key":"2026052722353761000_13.6.e011310.19","article-title":"Data from: Comparison of genetic and epigenetic profiles of periodontitis according to the presence of type 2 diabetes","volume":"5","author":"Kang","year":"2024","journal-title":"Gene Expression Omnibus"},{"key":"2026052722353761000_13.6.e011310.20","first-page":"181","article-title":"Data from: Single cell transcriptomic landscape of diabetic foot ulcers","volume":"13","author":"Theocharidis","year":"2022","journal-title":"Gene Expression Omnibus"},{"key":"2026052722353761000_13.6.e011310.21","first-page":"1397661","article-title":"Data from: Single-cell analysis of human PBMCs in healthy and type 2 diabetes populations: dysregulated immune networks in type 2 diabetes unveiled through single-cell profiling","volume":"15","author":"Gu","year":"2024","journal-title":"Gene Expression Omnibus"},{"key":"2026052722353761000_13.6.e011310.22","first-page":"424","article-title":"Data from: Immune phenotypic linkage between colorectal cancer and liver metastasis","volume":"40","author":"Liu","year":"2022","journal-title":"Gene Expression Omnibus"},{"key":"2026052722353761000_13.6.e011310.23","first-page":"134","article-title":"Data from: Spatiotemporal Immune Landscape of Colorectal Cancer Liver Metastasis at Single-Cell Level","volume":"12","author":"Wu","year":"2022","journal-title":"The National Omics Data Encyclopedia"},{"key":"2026052722353761000_13.6.e011310.24","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096"},{"key":"2026052722353761000_13.6.e011310.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2019.03.003"},{"key":"2026052722353761000_13.6.e011310.26","doi-asserted-by":"crossref","DOI":"10.1186\/s13059-017-1382-0","article-title":"SCANPY: large-scale single-cell gene expression data analysis","volume":"19","author":"Wolf","year":"2018","journal-title":"Genome Biol"},{"key":"2026052722353761000_13.6.e011310.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0229-21"},{"key":"2026052722353761000_13.6.e011310.28","doi-asserted-by":"crossref","unstructured":"Korotkevich G , Sukhov V , Budin N , et al . Fast gene set enrichment analysis. bioRxiv [Preprint] 2016. doi:10.1101\/060012","DOI":"10.1101\/060012"},{"key":"2026052722353761000_13.6.e011310.29","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"2026052722353761000_13.6.e011310.30","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4402"},{"key":"2026052722353761000_13.6.e011310.31","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat Commun"},{"key":"2026052722353761000_13.6.e011310.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-021-01274-5"},{"key":"2026052722353761000_13.6.e011310.33","doi-asserted-by":"crossref","DOI":"10.1038\/srep30656","article-title":"Hepatic immunophenotyping for streptozotocin-induced hyperglycemia in mice","volume":"6","author":"Lee","year":"2016","journal-title":"Sci Rep"},{"key":"2026052722353761000_13.6.e011310.34","doi-asserted-by":"publisher","DOI":"10.1126\/science.1202947"},{"key":"2026052722353761000_13.6.e011310.35","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2020-000957","article-title":"TIGIT in cancer immunotherapy","volume":"8","author":"Chauvin","year":"2020","journal-title":"J Immunother Cancer"},{"key":"2026052722353761000_13.6.e011310.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0346-9"},{"key":"2026052722353761000_13.6.e011310.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.02.009"},{"key":"2026052722353761000_13.6.e011310.38","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-00490-y"},{"key":"2026052722353761000_13.6.e011310.39","doi-asserted-by":"crossref","DOI":"10.1186\/s13046-024-03204-7","article-title":"Exosomal miR-106a-5p from highly metastatic colorectal cancer cells drives liver metastasis by inducing macrophage M2 polarization in the tumor microenvironment","volume":"43","author":"Liang","year":"2024","journal-title":"J Exp Clin Cancer Res"},{"key":"2026052722353761000_13.6.e011310.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2023.04.013"},{"key":"2026052722353761000_13.6.e011310.41","doi-asserted-by":"publisher","DOI":"10.1172\/JCI87252"},{"key":"2026052722353761000_13.6.e011310.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01267-2"},{"key":"2026052722353761000_13.6.e011310.43","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)02317-1"},{"key":"2026052722353761000_13.6.e011310.44","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21772"},{"key":"2026052722353761000_13.6.e011310.45","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20141836"},{"key":"2026052722353761000_13.6.e011310.46","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.070537"},{"key":"2026052722353761000_13.6.e011310.47","doi-asserted-by":"crossref","DOI":"10.1016\/j.tranon.2020.100825","article-title":"Tumor-associated neutrophils suppress antitumor immunity of NK cells through the PD-L1\/PD-1 axis","volume":"13","author":"Sun","year":"2020","journal-title":"Transl Oncol"},{"key":"2026052722353761000_13.6.e011310.48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1002372107"},{"key":"2026052722353761000_13.6.e011310.49","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-201605"},{"key":"2026052722353761000_13.6.e011310.50","doi-asserted-by":"publisher","DOI":"10.1021\/jm5003167"},{"key":"2026052722353761000_13.6.e011310.51","doi-asserted-by":"crossref","unstructured":"Kang Y , Zhu X , Lin Z , et al . Compare the Diagnostic and Prognostic Value of MLR, NLR and PLR in CRC Patients. Clin Lab 2021;67. doi:10.7754\/Clin.Lab.2021.201130","DOI":"10.7754\/Clin.Lab.2021.201130"},{"key":"2026052722353761000_13.6.e011310.52","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-01189-6"},{"key":"2026052722353761000_13.6.e011310.53","doi-asserted-by":"crossref","first-page":"822","DOI":"10.5306\/wjco.v13.i10.822","article-title":"Neutrophil-to-lymphocyte ratio as a prognostic factor for survival in patients with colorectal liver metastases: A systematic review","volume":"13","author":"Papakonstantinou","year":"2022","journal-title":"World J Clin Oncol"},{"key":"2026052722353761000_13.6.e011310.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjsurg.2020.05.003"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2024-011310","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T05:35:49Z","timestamp":1779946549000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2024-011310"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6]]},"references-count":54,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,22]]},"published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1136\/jitc-2024-011310"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2024-011310","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6]]}}}