{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T18:11:17Z","timestamp":1778177477052,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,5]]},"group-title":"Cancer Biology","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:00:00Z","timestamp":1777939200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Inflammation-driven tumor implantation, such as port-site metastasis (PSM) following laparoscopic gynecologic surgery and peritoneal seeding during post-surgical recurrence, represents an aggressive clinical problem that remains poorly understood and lacks targeted therapies. To address this, we developed a non-surgical Mesothelium-Inflammation\/Injury-Metastasis (MIM) model and investigated the role of the IL-1\u03b2\/IL1R1\/MYD88\/IRAK1\/4 axis and NLRP3 in epithelial ovarian cancer (EOC) seeding at inflamed or injured sites. This model created by a needle injury recapitulates inflammation-driven peritoneal seeding and mimics PSM and inflammation associated dissemination in peritoneum during recurrence. Seeding was dependent on Il1r1 but not Nlrp3, despite its role in regulating IL-1\u03b2 production, as Il1ra\u207b\/\u207b and Nlrp3\u207b\/\u207b mice phenocopied wild-type C57BL\/6 mice. Given the limited antitumor efficacy of IL-1\u03b2\u2013targeting agents such as Anakinra and Canakinumab, we focused on IRAK4 as a therapeutic target. IRAK4 knockdown significantly prolonged survival, reduced tumor cell adhesion, downregulated E-cadherin and Wnt4, and induced S-phase\/mitotic arrest. This led to the development of UR241-2, a small-molecule IRAK4 inhibitor, which was validated through molecular simulations, hotspot analysis, nanoBRET, global kinome profiling, and NF-\u03ba\u03b2 reporter assays. UR241-2 inhibited NF-\u03ba\u03b2 nuclear translocation and blocked IL-1\u03b2\u2013induced IRAK4 phosphorylation. UR241-2 exhibited favorable drug-like properties, including absence of CYP or hERG inhibition, and acceptable CaCo-2 permeability, plasma protein binding, microsomal stability, and pharmacokinetics. In vivo, UR241-2 reduced SKOV3 xenograft growth, suppressed mesothelial seeding, and increased MHC-II\u207a macrophages and activated neutrophils in syngeneic high-grade epithelial ovarian HGS3 tumors. RNA-seq revealed enrichment of neutrophil activation signatures and suppression of extracellular matrix (ECM) gene programs. Together, these findings establish a role for the IL-1\u03b2\/IL1R1\/IRAK4 axis in inflammation-driven PSM and peritoneal seeding and ECM regulation in EOC, and demonstrate that IRAK4 inhibition activates antitumor immune responses, providing a therapeutic strategy to block metastatic seeding and improve tumor control.<\/jats:p>","DOI":"10.64898\/2026.04.30.722105","type":"posted-content","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T22:36:49Z","timestamp":1778020609000},"source":"Crossref","is-referenced-by-count":0,"title":["IL1\u03b2\/IL1R1\/IRAK4 Drives Inflammatory Ovarian Cancer Seeding at the inflamed sites and Is Reversed by an IRAK4 inhibitor UR241-2"],"prefix":"10.64898","author":[{"given":"John P.","family":"Miller","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester, Rochester, NY, USA,14642"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyu 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