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Here, we identify cytokine motif\u2010containing, immunomodulatory bacterial proteins (CMCPs) as a special category of bacterial proteins in both bacterial genomes and gut metagenomes using Hidden Markov Models (HMMs). We further find eight colorectal cancer\u2011associated CMCPs differentially enriched in patients or healthy controls. Engineered\n                    <jats:italic>E. coli<\/jats:italic>\n                    Nissle 1917 (EcN) expressing selected CMCPs administered to\n                    <jats:italic>\n                      Apc\n                      <jats:sup>min\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mice selectively colonize intestinal tumors, deliver functional CMCPs in situ, and elicit significant antitumor immune responses while reducing tumor burden. In vitro, purified CMCPs modulate mouse splenic T cells, bone marrow\u2011derived macrophages and dendritic cells. Our findings indicate that bacterially encoded CMCPs can directly modulate tumor immunity and serve as microbiota\u2011derived proteins as candidate immunomodulators, which can further be applied in microbiome\u2010mediated immune therapies for CRC.\n                  <\/jats:p>","DOI":"10.1002\/advs.202520332","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T10:49:54Z","timestamp":1774262994000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identifying Cytokine Motif\u2010Containing, Immunomodulatory Bacterial Proteins in Human Gut Microbiome"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8615-1816","authenticated-orcid":false,"given":"Ziyu","family":"Wang","sequence":"first","affiliation":[{"name":"Laboratory of Pathogen Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences  Beijing 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