{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:46:46Z","timestamp":1793321206124,"version":"4.5.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019155","name":"Nanjing Drum Tower Hospital","doi-asserted-by":"publisher","award":["2022-LCYJ-MS-26"],"award-info":[{"award-number":["2022-LCYJ-MS-26"]}],"id":[{"id":"10.13039\/501100019155","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Synchronous colorectal cancer liver metastasis (CRCLM) is closely associated with poor prognosis; however, the precise factors contributing to this adverse outcome remain uncertain. In the tumor microenvironment of CRCLM, tumor budding (TB) serves as a morphologic hallmark of invasive potential, while tertiary lymphoid structures (TLS) are indicative of organized anti-tumor immune contexture. This study aimed to integrate these biomarkers to predict the survival of patients with CRCLM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This multicenter retrospective study enrolled 107 patients with synchronous CRCLM who underwent curative resection for colorectal cancer. An external validation cohort including 30 patients with CRCLM were also employed. The density of TLS and the TB count were quantified via hematoxylin and eosin (H&amp;amp;E) staining and immunohistochemical (IHC) staining on primary tumor specimens. Relationships between clinicopathological data, overall survival (OS), and recurrence-free survival (RFS) were analyzed. The TLS\/TB index was derived by integrating TLS and TB densities. The clinical role and prognostic value of the TLS\/TB index in patients with CRCLM were analyzed, and a nomogram was constructed to predict the 3-year survival of patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>High TLS density was significantly associated with prolonged overall survival (OS; p &amp;lt; 0.001) and recurrence-free survival (RFS; p&amp;lt; 0.001) in patients with CRCLM. Conversely, higher TB grade predicted a worse OS (p &amp;lt; 0.001) and RFS (p &amp;lt; 0.001). The TLS and TB exhibited a significant inverse correlation (r = -0.581, p &amp;lt; 0.001). The TLS\/TB index demonstrated superior prognostic accuracy in the training cohort (AUC\u00a0=\u00a00.89) compared with histological differentiation (AUC\u00a0=\u00a00.70), TB grade (AUC\u00a0=\u00a00.85) and TLS density (AUC\u00a0=\u00a00.80), with consistent performance in the validation cohort. Calibration curves showed acceptable agreement between predicted and observed survival in both cohorts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These results demonstrated that tumor budding and tertiary lymphoid structures are inversely correlated in CRCLM. Furthermore, the TLS\/TB-based nomogram may effectively enhanced the accuracy of prognosis prediction in patients with CRCLM, potentially facilitating the formulation of individualized treatment strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1776493","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T05:43:55Z","timestamp":1778564635000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Comprehensive analysis based on tertiary lymphoid structures and tumor budding predicts survival rates in colorectal cancer patients with synchronous liver metastases"],"prefix":"10.3389","volume":"17","author":[{"given":"Jianzhi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University","place":["Nanjing, China"]},{"name":"Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjie","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University","place":["Nanjing, China"]},{"name":"Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University","place":["Nanjing, China"]},{"name":"Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Colorectal Cancer Center, Department of General Surgery, Jiangsu Cancer Hospital, Cancer Research Institute, Cancer Hospital of Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofei","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University","place":["Nanjing, China"]},{"name":"Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghuan","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University","place":["Nanjing, China"]},{"name":"Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA: A Cancer J For Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2023.01.003","article-title":"Metastatic colorectal cancer: Mechanisms and emerging therapeutics","volume":"44","author":"Shin","year":"2023","journal-title":"Trends Pharmacol Sci"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.23736\/s2724-5691.24.10363-2","article-title":"Evolution and current trends in the management of colorectal cancer liver metastasis","volume":"79","author":"Leiphrakpam","year":"2024","journal-title":"Minerva Surg"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejso.2007.09.025","article-title":"Monoclonal antibodies in the treatment of advanced colorectal cancer","volume":"33","author":"Capdevila","year":"2007","journal-title":"Eur J Surg Oncol (EJSO)"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2025.5728","article-title":"Pathogenetic development, diagnosis and clinical therapeutic approaches for liver metastasis from colorectal cancer (review)","volume":"66","author":"Jin","year":"2025","journal-title":"Int J Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15072113","article-title":"Pushing the limits of surgical resection in colorectal liver metastasis: How far can we go","volume":"15","author":"Calderon Novoa","year":"2023","journal-title":"Cancers"},{"key":"B7","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.trsl.2024.04.003","article-title":"Targeting the devil: Strategies against cancer-associated fibroblasts in colorectal cancer","volume":"270","author":"Chen","year":"2024","journal-title":"Trans Res"},{"key":"B8","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1038\/s41419-024-06726-2","article-title":"Role of T cells in liver metastasis","volume":"15","author":"Wu","year":"2024","journal-title":"Cell Death Dis"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2020.107753","article-title":"Tumor microenvironment as a therapeutic target in cancer","volume":"221","author":"Xiao","year":"2021","journal-title":"Pharmacol Ther"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17060953","article-title":"Liver extracellular matrix in colorectal liver metastasis","volume":"17","author":"Morabito","year":"2025","journal-title":"Cancers"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-020-06203-8","article-title":"Comparison of immune microenvironment between colon and liver metastatic tissue in colon cancer patients with liver metastasis","volume":"66","author":"Zhou","year":"2020","journal-title":"Digestive Dis Sci"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2023.108522","article-title":"Cancer metastasis: Molecular mechanisms and clinical perspectives","volume":"250","author":"Khan","year":"2023","journal-title":"Pharmacol Ther"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.12.053","article-title":"Predictive role of tumor budding in T1 colorectal cancer lymph node metastasis","volume":"161","author":"Huang","year":"2021","journal-title":"Gastroenterology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0422-y","article-title":"Tumour budding in solid cancers","volume":"18","author":"Lugli","year":"2020","journal-title":"Nat Rev Clin Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1097\/js9.0000000000000483","article-title":"Prediction values of tertiary lymphoid structures in the prognosis of patients with left- and right-sided colon cancer: A multicenter propensity score-matched study","volume":"109","author":"Mao","year":"2023","journal-title":"Int J Surg"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1042\/cs20210886","article-title":"Molecular mechanisms of tumour budding and its association with microenvironment in colorectal cancer","volume":"136","author":"Hatthakarnkul","year":"2022","journal-title":"Clin Sci"},{"key":"B17","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1007\/s00384-023-04423-8","article-title":"Tumor budding and the prognosis of patients with metastatic colorectal cancer: A meta-analysis","volume":"38","author":"Qu","year":"2023","journal-title":"Int J Colorectal Dis"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1394505","article-title":"Tertiary lymphoid structures: New immunotherapy biomarker","volume":"15","author":"Yang","year":"2024","journal-title":"Front Immunol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1038\/s41392-024-01947-5","article-title":"Tertiary lymphoid structures in diseases: Immune mechanisms and therapeutic advances","volume":"9","author":"Zhao","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-006425","article-title":"Localization and density of tertiary lymphoid structures associate with molecular subtype and clinical outcome in colorectal cancer liver metastases","volume":"11","author":"Zhang","year":"2023","journal-title":"J Immunother Cancer"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1473969","article-title":"Tertiary lymphoid structures: Exploring opportunities to improve immunotherapy in ovarian cancer","volume":"16","author":"Varghese","year":"2025","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1080\/1744666x.2024.2380892","article-title":"Tumor-associated tertiary lymphoid structures in cancer: Implications for immunotherapy","volume":"20","author":"Langouo Fontsa","year":"2024","journal-title":"Expert Rev Clin Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1256355","article-title":"The prognostic value of the tertiary lymphoid structure in gastrointestinal cancers","volume":"14","author":"Yu","year":"2023","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2025.217491","article-title":"Tertiary lymphoid structures as a biomarker in immunotherapy and beyond: Advancing towards clinical application","volume":"613","author":"Cui","year":"2025","journal-title":"Cancer Lett"},{"key":"B25","doi-asserted-by":"publisher","first-page":"100546","DOI":"10.1016\/j.medj.2024.10.023","article-title":"Tertiary lymphoid structures and cancer immunotherapy: From bench to bedside","volume":"6","author":"Peyraud","year":"2025","journal-title":"Med"},{"key":"B26","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1186\/s13046-023-02729-7","article-title":"Liver metastasis from colorectal cancer: Pathogenetic development, immune landscape of the tumour microenvironment and therapeutic approaches","volume":"42","author":"Wang","year":"2023","journal-title":"J Exp Clin Cancer Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.70389\/PJS.100081","article-title":"Revised strengthening the reporting of cohort, cross-sectional and case-control studies in surgery (Strocss) guideline: An update for the age of artificial intelligence","volume":"2","author":"Riaz","year":"2025","journal-title":"Premier J Sci"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf9419","article-title":"Tertiary lymphoid structures in cancer","volume":"375","author":"Schumacher","year":"2022","journal-title":"Science"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/cas.12530","article-title":"Tumor budding in colorectal carcinoma assessed by cytokeratin immunostaining and budding areas: Possible involvement of C-Met","volume":"105","author":"Satoh","year":"2014","journal-title":"Cancer Sci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2017.46","article-title":"Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (Itbcc) 2016","volume":"30","author":"Lugli","year":"2017","journal-title":"Mod Pathol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1177\/0013164418817803","article-title":"Evaluation of variance inflation factors in regression models using latent variable modeling methods","volume":"79","author":"Marcoulides","year":"2019","journal-title":"Educ Psychol Meas"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3892\/or.2017.5531","article-title":"Current status and future perspectives on treatment of liver metastasis in colorectal cancer","volume":"37","author":"Al Bandar","year":"2017","journal-title":"Oncol Rep"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32982","article-title":"12\u2010Chemokine signature, a predictor of tumor recurrence in colorectal cancer","volume":"147","author":"Tokunaga","year":"2020","journal-title":"Int J Cancer"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s13402-024-00975-1","article-title":"Tertiary lymphoid structures and their therapeutic implications in cancer","volume":"47","author":"Chen","year":"2024","journal-title":"Cell Oncol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2022.101703","article-title":"Activation of B cells in tertiary lymphoid structures in cancer: Anti-tumor or anti-self","volume":"65","author":"Fridman","year":"2023","journal-title":"Semin Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2025.115572","article-title":"Induction of tertiary lymphoid structures in tumor microenvironment to improve anti-tumoral immune checkpoint blockade efficacy","volume":"225","author":"Vion","year":"2025","journal-title":"Eur J Cancer"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/jcm5050051","article-title":"Tumor budding: The name is Emt. Partial Emt","volume":"5","author":"Grigore","year":"2016","journal-title":"J Clin Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1776493\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T05:43:56Z","timestamp":1778564636000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1776493\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,12]]},"references-count":37,"alternative-id":["10.3389\/fimmu.2026.1776493"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1776493","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,12]]},"article-number":"1776493"}}