{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T06:04:45Z","timestamp":1789538685056,"version":"build-2803163510"},"reference-count":90,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"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>Colorectal cancer liver metastasis (CRLM) develops within a liver-specific immune and stromal microenvironment, yet the natural killer (NK)-cell adaptations associated with this metastatic niche remain incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated human single-cell RNA sequencing, an exploratory murine cross-species comparison, spatial transcriptomics, bulk transcriptomic cohorts, donor-level pseudobulk analyses, cell-cell communication, pseudotime and in silico perturbation analyses, together with multiplex immunofluorescence, conditioned-medium assays, ELISA and immunoblotting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Across 73,486 cells from six anatomical sites, NK cells showed lower relative representation within the recovered T\/NK compartment in primary tumors and liver metastases, while the residual compartment showed inflammatory remodeling. NK-cell reclustering identified CD56-associated and CD16-associated CCL4 source clusters that were analyzed jointly as a CCL4-enriched NK-cell transcriptional state\u00a0characterized by NF-\u03baB, TNF, MAPK and JAK-STAT programs. In paired GSE164522 samples from 10 patients, this state was independently recovered, with nominally higher CCL4-associated signal in liver metastases than in primary tumors that did not remain significant after Benjamini-Hochberg correction. Spatial and communication analyses associated the state with SPP1-positive macrophage and stromal programs without establishing causality. Tissue imaging, conditioned-medium assays, ELISA and immunoblotting provided complementary marker-level and model-system support for CCL4-associated inflammatory activity and NF-\u03baB pathway responsiveness.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      CRLM is associated with altered NK-cell representation among recovered cells and a reproducible CCL4-enriched inflammatory NK-cell transcriptional state. Its association with inflammatory and myeloid-stromal programs across independent, spatial and model-system analyses provides a focused framework for future lineage-restricted and\n                      <jats:italic>in vivo<\/jats:italic>\n                      studies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1923511","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T05:31:34Z","timestamp":1789536694000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A CCL4-enriched NK-cell transcriptional state is associated with inflammatory and myeloid-stromal programs in colorectal cancer liver metastasis"],"prefix":"10.3389","volume":"17","author":[{"given":"Lihong","family":"Lin","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Intelligent Medical Image Computing, School of Artificial Intelligence, Nanjing University of Information Science and Technology","place":["Nanjing, China"]},{"name":"Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University","place":["Nanjing, China"]},{"name":"Department of Colorectal Surgery, Ningbo No. 2 Hospital","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Zhengyang","family":"Xu","sequence":"additional","affiliation":[{"name":"Jinling High School Hexi Campus","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochun","family":"Gu","sequence":"additional","affiliation":[{"name":"Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijian","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Center of Joint and Sports Medicine, Orthopedics Department, Zhongda Hospital, School of Medicine, Southeast University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Colorectal Surgery, Ningbo No. 2 Hospital","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlong","family":"Ming","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Intelligent Medical Image Computing, School of Artificial Intelligence, Nanjing University of Information Science and Technology","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3322\/caac.21820","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41572-021-00261-6","article-title":"Liver metastases","volume":"7","author":"Tsilimigras","year":"2021","journal-title":"Nat Rev Dis Primers"},{"key":"B3","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":"B4","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-0316","article-title":"Spatiotemporal immune landscape of colorectal cancer liver metastasis at single-cell level","volume":"12","author":"Wu","year":"2022","journal-title":"Cancer Discov"},{"key":"B5","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1016\/j.ccell.2022.02.013","article-title":"Immune phenotypic linkage between colorectal cancer and liver metastasis","volume":"40","author":"Liu","year":"2022","journal-title":"Cancer Cell"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adf5464","article-title":"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":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.1198687","article-title":"Innate or adaptive immunity? 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