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CAFs take on diverse phenotypes with distinct functions. Myofibroblastic CAFs (myCAFs) regulate extracellular matrix remodeling, while inflammatory CAFs (iCAFs) modulate immune infiltration. Further studies are required to validate biomarkers of CAF phenotypes and to identify means to therapeutically manipulate CAFs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Single-cell RNA sequencing analysis was used to identify markers of CAF phenotypes in CRC. CAF markers were validated and compared to clinical characteristics using patient-derived CAF cultures, fixed human CRC samples, and publicly available RNA sequencing data. Therapeutics were prioritized for their potential to inhibit the myCAF phenotype and nilotinib was selected for validation in patient-derived CAFs. Overall changes in CAFs were evaluated via RNA-seq, and results validated with in vitro experiments. Finally, the feasibility of altering CAF phenotypes to affect treatment response was evaluated in vivo\n                      <jats:italic>.<\/jats:italic>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Here we identify disease-specific markers of colorectal CAFs that are functionally distinct, biologically identifiable, correlate with clinically relevant markers of disease, and can be therapeutically altered in vivo. High stromal expression of myCAF markers correlated with reduced infiltration of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T lymphocytes into the epithelial compartment compared to tumors with high stromal expression of iCAF markers. Nilotinib treatment inhibited myogenesis regulators myocardin and myocardin-related transcription factor A, which correlated with reduced expression of myCAF markers and extracellular matrix proteins and decreased tumor size in colorectal cancer-bearing mice when combined with anti-PD-1 therapy. We also identified PD-1 as a potential molecule that activates myocardin and myCAF expression, indicating a potential mechanism for increased response to the combination with anti-PD-1 therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results highlight the feasibility of targeting CAF functions to improve therapeutic response, and support the investigation of nilotinib and anti-PD-1 therapy clinically.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03779-3","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T13:35:46Z","timestamp":1783690546000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Suppression of the myofibroblastic cancer-associated fibroblast phenotype to enhance anti-PD-1 response"],"prefix":"10.1186","volume":"45","author":[{"given":"Katherine A.","family":"Johnson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna E.L.","family":"Lippert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alec","family":"Cornelio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousef","family":"Gadalla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingqi","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean G.","family":"Kraus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip B.","family":"Emmerich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.","family":"Field","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa K.","family":"Steimle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheri A.","family":"Pasch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huy Q.","family":"Dinh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina A.","family":"Matkowskyj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dustin A.","family":"Deming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"3779_CR1","unstructured":"The American Cancer Society. 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For immunofluorescence (IF) analysis of representative human tumors and derivation of CAF cell lines, human samples were acquired through the University of Wisconsin (UW) Translational Science BioCore (UW IRB#2016\u2009\u2212\u20090934), UW Molecular Tumor Board Registry (UW IRB#2014\u2009\u2212\u20091370), or UW Rectal and Anal Cancer Registry (UW IRB#2018\u2009\u2212\u20090149).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"208"}}