{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:35:29Z","timestamp":1790634929895,"version":"4.1.0"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"content-version":"vor","delay-in-days":9,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Korea government","award":["NRF-2021R1A5A2030333"],"award-info":[{"award-number":["NRF-2021R1A5A2030333"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Mismatch repair-deficient (dMMR) colorectal cancers (CRCs) exhibit variable clinical responses to immune checkpoint inhibitors (ICIs) despite their high immunogenicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To investigate the molecular and spatial determinants of this heterogeneity, we analyzed five metastatic sites (colon, liver, peritoneum, left ovary, and right ovary) from a dMMR CRC patient treated with pembrolizumab using bulk and single-cell RNA sequencing combined with multiplex immunohistochemistry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Responsive lesions were characterized by enriched cytotoxic and interferon-\u03b3 signatures, greater CD8+ T-cell infiltration, and close spatial proximity between programmed death-ligand 1(PD-L1)+ tumor cells and M1-like macrophages. In contrast, resistant lesions demonstrated reduced effector cell presence and were enriched in immunosuppressive programs, including SPP1+ and CD163+ macrophages, noncanonical WNT5A\/B signaling, and TGF-\u03b2\u2013mediated matrix remodeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Collectively, these findings highlight the importance of spatial immune architecture and macrophage polarization in shaping ICI responses in dMMR CRC and underscore the need for spatial profiling to guide immunotherapy strategies in metastatic disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/immadv\/ltag001","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T12:42:38Z","timestamp":1767789758000},"source":"Crossref","is-referenced-by-count":2,"title":["Comprehensive spatial and immune profiling of metastatic mismatch repair\u2013deficient colorectal cancer reveals response to immunotherapy"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4819-7773","authenticated-orcid":false,"given":"Ilkyu","family":"Park","sequence":"first","affiliation":[{"name":"Department of Medicine, College of Medicine, Gachon University , Incheon 21565 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hari","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Gachon University Gil Medical Center , Incheon 21565 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se-Hee","family":"Kim","sequence":"additional","affiliation":[{"name":"Gachon Medical Research Institute, Gachon University Gil Medical Center , Incheon 21565 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YunJae","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Microbiology, College of Medicine, Gachon University, Department of Health Science and Technology, Gachon Advanced Institute for Health Science & Technology , Incheon ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won-Suk","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Surgery, Gil Medical Center, Gachon University College of Medicine , Incheon ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"2026041811120832800_ltag001-B1","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1007\/s00428-024-03773-0","article-title":"Correction to: molecular pathological classification of colorectal cancer-an update","volume":"484","author":"Dunne","year":"2024","journal-title":"Virchows Arch"},{"key":"2026041811120832800_ltag001-B2","doi-asserted-by":"publisher","first-page":"73","DOI":"10.4161\/cbt.3.1.590","article-title":"Evaluation of microsatellite instability, hMLH1 expression and hMLH1 promoter hypermethylation in defining the MSI phenotype of colorectal cancer","volume":"3","author":"Arnold","year":"2004","journal-title":"Cancer Biol Ther"},{"key":"2026041811120832800_ltag001-B3","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1136\/gut.47.1.148","article-title":"DNA mismatch repair genes and colorectal cancer","volume":"47","author":"Wheeler","year":"2000","journal-title":"Gut"},{"key":"2026041811120832800_ltag001-B4","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.1002\/ijc.25265","article-title":"Combined analysis of specific KRAS mutation, BRAF and microsatellite instability identifies prognostic subgroups of sporadic and hereditary colorectal cancer","volume":"127","author":"Zlobec","year":"2010","journal-title":"Int J Cancer"},{"key":"2026041811120832800_ltag001-B5","doi-asserted-by":"publisher","first-page":"827596","DOI":"10.3389\/fonc.2022.827596","article-title":"Lymphocytes infiltration and expression of PD-1 and PD-L1 in colorectal cancer between HIV-infected and non-HIV-infected patients: a propensity score matched cohort study","volume":"12","author":"Cao","year":"2022","journal-title":"Front Oncol"},{"key":"2026041811120832800_ltag001-B6","doi-asserted-by":"publisher","first-page":"110331","DOI":"10.1016\/j.celrep.2022.110331","article-title":"PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes","volume":"38","author":"Nagasaki","year":"2022","journal-title":"Cell Rep"},{"key":"2026041811120832800_ltag001-B7","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1016\/S1470-2045(17)30422-9","article-title":"Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study","volume":"18","author":"Overman","year":"2017","journal-title":"Lancet Oncol"},{"key":"2026041811120832800_ltag001-B8","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1053\/j.gastro.2024.08.003","article-title":"High pathological response rate after neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer (NICHE-2 study)","volume":"168","author":"Sallinen","year":"2025","journal-title":"Gastroenterology"},{"key":"2026041811120832800_ltag001-B9","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.4143\/crt.2020.218","article-title":"A phase II study of avelumab monotherapy in patients with mismatch repair-deficient\/microsatellite instability-high or POLE-mutated metastatic or unresectable colorectal cancer","volume":"52","author":"Kim","year":"2020","journal-title":"Cancer Res Treat"},{"key":"2026041811120832800_ltag001-B10","doi-asserted-by":"publisher","first-page":"2038","DOI":"10.1002\/ijc.33966","article-title":"Phase II study of durvalumab monotherapy in patients with previously treated microsatellite instability-high\/mismatch repair-deficient or POLE-mutated metastatic or unresectable colorectal cancer","volume":"150","author":"Oh","year":"2022","journal-title":"Int J Cancer"},{"key":"2026041811120832800_ltag001-B11","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s13046-025-03303-z","article-title":"VSIG4(+) tumor-associated macrophages mediate neutrophil infiltration and impair antigen-specific immunity in aggressive cancers through epigenetic regulation of SPP1","volume":"44","author":"Pan","year":"2025","journal-title":"J Exp Clin Cancer Res"},{"key":"2026041811120832800_ltag001-B12","doi-asserted-by":"publisher","first-page":"1573917","DOI":"10.3389\/fimmu.2025.1573917","article-title":"Targeting tumor-associated macrophages in colon cancer: mechanisms and therapeutic strategies","volume":"16","author":"Xiang","year":"2025","journal-title":"Front Immunol"},{"key":"2026041811120832800_ltag001-B13","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1007\/s10555-018-9731-3","article-title":"mPGES-1 and ALOX5\/-15 in tumor-associated macrophages","volume":"37","author":"Weigert","year":"2018","journal-title":"Cancer Metastasis Rev"},{"key":"2026041811120832800_ltag001-B14","doi-asserted-by":"publisher","first-page":"4015","DOI":"10.1172\/JCI45862","article-title":"Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice","volume":"121","author":"Lu","year":"2011","journal-title":"J Clin Invest"},{"key":"2026041811120832800_ltag001-B15","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1186\/s12957-021-02299-y","article-title":"Prognostic significance of CD163 + tumor-associated macrophages in colorectal cancer","volume":"19","author":"Xue","year":"2021","journal-title":"World J Surg Oncol"},{"key":"2026041811120832800_ltag001-B16","doi-asserted-by":"publisher","first-page":"2407","DOI":"10.1002\/ijc.32228","article-title":"Bridging genomics and phenomics of gastric carcinoma","volume":"145","author":"Cho","year":"2019","journal-title":"Int J Cancer"},{"key":"2026041811120832800_ltag001-B17","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"2026041811120832800_ltag001-B18","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1186\/1471-2105-12-323","article-title":"RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome","volume":"12","author":"Li","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"2026041811120832800_ltag001-B19","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive integration of single-cell data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"2026041811120832800_ltag001-B20","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat Methods"},{"key":"2026041811120832800_ltag001-B21","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s11864-016-0414-4","article-title":"Deficient mismatch repair and the role of immunotherapy in metastatic colorectal cancer","volume":"17","author":"Quiroga","year":"2016","journal-title":"Curr Treat Options Oncol"},{"key":"2026041811120832800_ltag001-B22","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.6004\/jnccn.2019.7308","article-title":"Comparison of mismatch repair Status between primary and matched metastatic sites in patients with colorectal cancer","volume":"17","author":"He","year":"2019","journal-title":"J Natl Compr Canc Netw"},{"key":"2026041811120832800_ltag001-B23","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1126\/science.aan6733","article-title":"Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade","volume":"357","author":"Le","year":"2017","journal-title":"Science"},{"key":"2026041811120832800_ltag001-B24","doi-asserted-by":"publisher","first-page":"86","DOI":"10.3389\/fonc.2018.00086","article-title":"Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations","volume":"8","author":"Seidel","year":"2018","journal-title":"Front Oncol"},{"key":"2026041811120832800_ltag001-B25","doi-asserted-by":"publisher","first-page":"1537631","DOI":"10.3389\/fimmu.2025.1537631","article-title":"The role of intestinal macrophage polarization in colitis-associated colon cancer","volume":"16","author":"Deng","year":"2025","journal-title":"Front Immunol"},{"key":"2026041811120832800_ltag001-B26","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1200\/JCO.2017.76.9901","article-title":"Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient\/microsatellite instability-high metastatic colorectal cancer","volume":"36","author":"Overman","year":"2018","journal-title":"J Clin Oncol"},{"key":"2026041811120832800_ltag001-B27","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1158\/1078-0432.CCR-18-1851","article-title":"The immunoscore: colon cancer and beyond","volume":"26","author":"Angell","year":"2020","journal-title":"Clin Cancer Res"},{"key":"2026041811120832800_ltag001-B28","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1016\/S1470-2045(19)30027-0","article-title":"Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial","volume":"20","author":"Eng","year":"2019","journal-title":"Lancet Oncol"}],"container-title":["Immunotherapy Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/immunotherapyadv\/advance-article-pdf\/doi\/10.1093\/immadv\/ltag001\/66320381\/ltag001.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/immunotherapyadv\/article-pdf\/6\/1\/ltag001\/66320381\/ltag001.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/immunotherapyadv\/article-pdf\/6\/1\/ltag001\/66320381\/ltag001.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T15:12:13Z","timestamp":1776525133000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/immunotherapyadv\/article\/doi\/10.1093\/immadv\/ltag001\/8417750"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,31]]},"references-count":28,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,12,31]]}},"URL":"https:\/\/doi.org\/10.1093\/immadv\/ltag001","relation":{},"ISSN":["2732-4303"],"issn-type":[{"value":"2732-4303","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026]]},"published":{"date-parts":[[2025,12,31]]},"article-number":"ltag001"}}