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Given these unmet clinical needs, novel targeted therapeutics are urgently required to improve advanced PCa patient outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we examined the expression of integrin subtypes, particularly pan-\u03b1v integrins and \u03b15\u03b21, in prostate cancertumor samples and cell lines using immunohistochemistry (IHC) and Western blotting. Based on rational drug design, we synthesized a first-in-class, orally bioavailable, non-RGD pan-\u03b1v\/\u03b15\u03b21 integrin antagonist, C19-9N, and characterized it through homology modeling, molecular docking, surface plasmon resonance (SPR), and microscale thermophoresis (MST). The antitumor activity of C19-9N was evaluated in vitro (via assays of cell viability, migration and invasion) and in vivo using multiple models, including subcutaneous xenografts of CRPC, bone-metastatic xenograft models established by intratibial and intracardiac injection, and patient-derived xenografts (PDXs) of NEPC. The in vivo safety and pharmacokinetic profile of C19-9N were also assessed. Mechanistically, single-cell RNA sequencing (scRNA-seq) was employed to uncover the regulatory effects of C19-9N on infiltrating immune cells within the tumor microenvironment, which were further validated through multiplex immunofluorescence and bone marrow-derived macrophage-mediated phagocytosis assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>C19-9N targeting pan-\u03b1v and \u03b15\u03b21 integrin circumvented potential compensatory resistance mediated by integrin subtype switching. C19-9N disrupted extracellular matrix (ECM)-integrin biochemical and mechanical signaling, thereby suppressing cancer stem cell (CSC) self-renewal and epithelial-to-mesenchymal transition (EMT). Mechanistically, C19-9N inhibited PI3K\/AKT and STAT3 signaling pathways to block alternative splicing of AR-V7, and modulated Survivin and c-Myc to enhance enzalutamide sensitivity. Additionally, it remodeled TME by repolarizing tumor-associated macrophages (TAMs) toward a pro-inflammatory phenotype and downregulating CD47-mediated immune escape. In preclinical models, C19-9N overcame enzalutamide resistance in CRPC xenografts, suppressed bone metastatic progression, and exhibited superior efficacy to platinum\/taxane therapies in NEPC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Collectively, by co-targeting oncogenic drivers and TME vulnerabilities, C19-9N heralds a transformative therapeutic paradigm with profound clinical potential for aggressive PCa.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12943-026-02686-7","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T14:27:26Z","timestamp":1778682446000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An orally bioavailable pan-\u03b1v\/\u03b15\u03b21 integrin antagonist prevents aggressive prostate cancer progression via suppressing both oncogenic signals and CD47-mediated immune escape"],"prefix":"10.1186","volume":"25","author":[{"given":"Yanlun","family":"Gu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingqi","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Teng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojiao","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binzhi","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jixin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuke","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimin","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuona","family":"Rong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaocong","family":"Pang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"2686_CR1","doi-asserted-by":"publisher","first-page":"e077738","DOI":"10.1136\/bmj-2023-077738","volume":"386","author":"S Vaccarella","year":"2024","unstructured":"Vaccarella S, Li M, Bray F, Kvale R, Serraino D, Lorenzoni V, et al. 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