{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T05:03:44Z","timestamp":1785301424170,"version":"3.55.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"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>Introduction<\/jats:title>\n                    <jats:p>Colorectal cancer (CRC) is a heterogeneous malignancy and a major cause of cancer-related mortality worldwide. Cancer-associated fibroblasts (CAFs) accumulate in tumors and correlate with poor patient survival, suggesting a central role in immune regulation. Patient-derived organoids (PDO) maintain the intra-tumoral cellular heterogeneity of the original tissue, thus, they represent one of the best methods to study human cancers. The tumor microenvironment (TME) contains diverse immune cell populations, including innate lymphoid cells (ILCs), yet how stromal components influence cytokine-driven tumor\u2013immune interactions remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>PDOs from CRC patients were used to screen TME-derived cytokines affecting tumor growth. Organoid-forming efficiency and signaling pathway activation were analyzed following cytokine stimulation in the presence or absence of CAFs. Tumor-infiltrating ILC subsets were characterized in patient samples, and co-culture systems were employed to assess cytokine production and stromal\u2013immune interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>IL-22 was identified as a cytokine that increased PDO-forming efficiency without activating fibroblasts. Although IL-22 typically signals through the JAK\u2013STAT pathway, it unexpectedly activates MAPK signaling in PDO cells. Interestingly, interferon-\u03b3 (IFN\u03b3) showed only partial cytotoxic effects on CRC cells. Tumor tissues contained both IFN\u03b3-producing ILC1 and IL-22\/IL-17A\u2013producing ILC3 populations. Co-culture with PDOs selectively induced IL-22, but not IL-17A, production in ILC3 cells. Importantly, IL-22 enhanced organoid formation only in the absence of CAFs, whereas IFN\u03b3 activity was largely unaffected by stromal context.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings demonstrate that CAFs modulate local immunity by selectively masking ILC3-derived IL-22 signaling while preserving ILC1-mediated IFN\u03b3 responses. This study emphasizes the importance of stromal context in interpreting cytokine function in CRC and reveals a previously unrecognized mechanism of stromal\u2013immune crosstalk within the TME.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1891700","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T04:47:01Z","timestamp":1785300421000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Fibroblasts selectively modulate immune cell-derived cytokine effects on tumor cells in colorectal cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Szabolcs","family":"Hajd\u00f3","sequence":"first","affiliation":[{"name":"Institute of Genetics, Cell- and Immunobiology, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt I.","family":"Koml\u00f3si","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Cell- and Immunobiology, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"\u00c9rsek","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Cell- and Immunobiology, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Idan","family":"Carmi","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Cell- and Immunobiology, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam\u00e1s","family":"T\u00f6lgyes","sequence":"additional","affiliation":[{"name":"Department of General Surgery and Surgical Oncology, Uzsoki Hospital","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n","family":"Wiener","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Cell- and Immunobiology, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-025-00872-1","article-title":"The immune microenvironment of colorectal cancer","volume":"25","author":"Kennel","year":"2025","journal-title":"Nat Rev Cancer"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2016.07.008","article-title":"Colorectal cancer subtypes: Developmental origin and microenvironmental regulation","volume":"2","author":"Fessler","year":"2016","journal-title":"Trends Cancer"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.126","article-title":"The consensus molecular subtypes of colorectal cancer","volume":"21","author":"Guinney","year":"2015","journal-title":"Nat Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3225","article-title":"Stromal gene expression defines poor-prognosis subtypes in colorectal cancer","volume":"47","author":"Calon","year":"2015","journal-title":"Nat Genet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.c.6866799.v2","article-title":"Colorectal cancer organoid-stroma biobank allows subtype-specific assessment of individualized therapy responses","volume":"13","author":"Farin","year":"2023","journal-title":"Cancer Discov"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01127-z","article-title":"Innate lymphoid cells and cancer","volume":"23","author":"Jacquelot","year":"2022","journal-title":"Nat Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nature14189","article-title":"The biology of innate lymphoid cells","volume":"517","author":"Artis","year":"2015","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.146006","article-title":"Therapeutic manipulation of innate lymphoid cells","volume":"6","author":"Cobb","year":"2021","journal-title":"JCI Insight"},{"key":"B9","doi-asserted-by":"publisher","first-page":"3035","DOI":"10.1038\/s41467-026-71085-9","article-title":"Tumor-infiltrating immature innate lymphoid cells in colorectal cancer are biased toward ILC1\/tissue-resident NK cell differentiation","volume":"17","author":"Marchalot","year":"2026","journal-title":"Nat Commun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.07.029","article-title":"Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer","volume":"184","author":"Goc","year":"2021","journal-title":"Cell"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-021-03949-w","article-title":"IFITM1 expression determines extracellular vesicle uptake in colorectal cancer","volume":"78","author":"Kelemen","year":"2021","journal-title":"Cell Mol Life Sci"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03052-1","article-title":"Extracellular vesicle release from intestinal organoids is modulated by Apc mutation and other colorectal cancer progression factors","volume":"76","author":"Szvicsek","year":"2019","journal-title":"Cell Mol Life Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241411585","article-title":"High CD142 level marks tumor-promoting fibroblasts with targeting potential in colorectal cancer","volume":"24","author":"Soos","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.04.003","article-title":"A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis","volume":"18","author":"Fujii","year":"2016","journal-title":"Cell Stem Cell"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08150-0","article-title":"Progressive plasticity during colorectal cancer metastasis","volume":"637","author":"Moorman","year":"2025","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"4251","DOI":"10.1038\/s41467-023-39953-w","article-title":"IL1R1(+) cancer-associated fibroblasts drive tumor development and immunosuppression in colorectal cancer","volume":"14","author":"Koncina","year":"2023","journal-title":"Nat Commun"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20162024","article-title":"Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer","volume":"214","author":"\u00d6hlund","year":"2017","journal-title":"J Exp Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2014.336","article-title":"IL-22 produced by cancer-associated fibroblasts promotes gastric cancer cell invasion via STAT3 and ERK signaling","volume":"111","author":"Fukui","year":"2014","journal-title":"Br J Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-025-02149-z","article-title":"The IL-22-oncostatin M axis promotes intestinal inflammation and tumorigenesis","volume":"26","author":"Cineus","year":"2025","journal-title":"Nat Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nature11535","article-title":"IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine","volume":"491","author":"Huber","year":"2012","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1038\/s42003-024-06601-y","article-title":"OLFM4 modulates intestinal inflammation by promoting IL-22(+)ILC3 in the gut","volume":"7","author":"Xing","year":"2024","journal-title":"Commun Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-009-0188-x","article-title":"Biology of interleukin-22","volume":"32","author":"Wolk","year":"2010","journal-title":"Semin Immunopathol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"716","DOI":"10.3892\/ol.2021.12977","article-title":"Interleukin-22 promotes PD-L1 expression via STAT3 in colon cancer cells","volume":"22","author":"Xi","year":"2021","journal-title":"Oncol Lett"},{"key":"B24","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1007\/s13205-023-03742-5","article-title":"Colorectal cancer tumor stem cells mediate bevacizumab resistance through the signal IL-22-STAT3 signaling pathway","volume":"13","author":"Qin","year":"2023","journal-title":"3 Biotech"},{"key":"B25","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1007\/s12672-024-01169-9","article-title":"IL-22 activates the PI3K-AKT pathway to promote colorectal cancer cell proliferation and metastasis","volume":"15","author":"Ruan","year":"2024","journal-title":"Discov Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.4251\/wjgo.v17.i8.108535","article-title":"Interleukin-22 promotes cancer stemness and chemotherapy resistance in colorectal cancer via epidermal growth factor receptor\/extracellular signal-regulated kinase pathway","volume":"17","author":"Ruan","year":"2025","journal-title":"World J Gastrointest Oncol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-022-00411-z","article-title":"Cancer-associated fibroblasts in the single-cell era","volume":"3","author":"Lavie","year":"2022","journal-title":"Nat Cancer"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1516","article-title":"The molecular classification of cancer-associated fibroblasts on a pan-cancer single-cell transcriptional atlas","volume":"13","author":"Chen","year":"2023","journal-title":"Clin Transl Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2025.11.008","article-title":"Group 3 innate lymphoid cells: Guardians of intestinal homeostasis","volume":"47","author":"Hao","year":"2025","journal-title":"Trends Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00676","article-title":"Group 3 ILCs: Peacekeepers or troublemakers? What's your gut telling you","volume":"10","author":"Pantazi","year":"2019","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-01024-x","article-title":"Reciprocal transcription factor networks govern tissue-resident ILC3 subset function and identity","volume":"22","author":"Fiancette","year":"2021","journal-title":"Nat Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.11.005","article-title":"Human innate lymphoid cell subsets possess tissue-type based heterogeneity in phenotype and frequency","volume":"46","author":"Simoni","year":"2017","journal-title":"Immunity"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1254\/jpssuppl.wcp2018.0_sy78-2","article-title":"Subsets of ILC3-ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues","volume":"20","author":"Colonna","year":"2019","journal-title":"Nat Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00566-3","article-title":"Interferon-gamma: Teammate or opponent in the tumour microenvironment","volume":"22","author":"Gocher","year":"2022","journal-title":"Nat Rev Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.70675\/ac790b4cz9f35z418cz89f3zeb164a5bcb06","article-title":"Bystander IFN-gamma activity promotes widespread and sustained cytokine signaling altering the tumor microenvironment","volume":"1","author":"Thibaut","year":"2020","journal-title":"Nat Cancer"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.12.010","article-title":"T cell-derived interleukin-22 drives the expression of CD155 by cancer cells to suppress NK cell function and promote metastasis","volume":"56","author":"Briukhovetska","year":"2023","journal-title":"Immunity"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-0636-z","article-title":"Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer","volume":"52","author":"Lee","year":"2020","journal-title":"Nat Genet"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.08.003","article-title":"Spatially organized multicellular immune hubs in human colorectal cancer","volume":"184","author":"Pelka","year":"2021","journal-title":"Cell"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1891700\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T04:47:03Z","timestamp":1785300423000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1891700\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,29]]},"references-count":38,"alternative-id":["10.3389\/fimmu.2026.1891700"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1891700","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,29]]},"article-number":"1891700"}}