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Alarmins, endogenous, stress-induced molecules, serve as early warning signals triggering immune responses. The human RNASET2 protein has demonstrated both oncosuppressive and immunoregulatory functions across various cancer types, yet its role as an oncosuppressor or alarmin-like molecule in prostate cancer (PCa) is unexplored. Here, we investigated the effects of the human RNASET2 alarmin in two different human PCa cell lines focusing on cell proliferation, colony formation, adhesion, migration rates, and release of soluble immune-modulatory factors. In vivo studies were also carried out on nude mice to assess the immune regulatory impact. Our findings indicate that RNASET2 overexpression reduced cell proliferation and colony formation in 22Rv1 cells, through downregulation of cyclin D1. RNASET2 overexpression in 22Rv1 cells was also associated with decreased levels of <jats:italic>TWIST<\/jats:italic>,<jats:italic> CTNNB1<\/jats:italic>,<jats:italic> YAP<\/jats:italic>,<jats:italic> and MMP-9<\/jats:italic>. By contrast, PC-3 cells were largely unresponsive to RNASET2. RNASET2 overexpression also promoted the release of soluble factors related to monocyte\/macrophage recruitment\/activation and cytokines\/chemokines, linked to immune cell-mediated anti-tumor responses. This effect was more pronounced in RNASET2-overexpressing 22Rv1 cells and involved both innate (NK cells, dendritic cells) and adaptive (T cells) immune activation, compared to PC-3 cells. RNASET2 overexpression also affected the cytoskeletal organization in both PCa models. RNASET2 overexpression in vivo induced a shift toward M1-like macrophage polarization pattern, while decreasing the M2-like polarization in mice challenged with 22Rv1 cells, indicating a potential tumor-suppressive role in PCa. Finally, silencing of RNASET2 in THP-1 macrophages unveiled their phagocytic activities against PCa cells. Our findings underscore the RNASET2\u2019s dual functionality, acting through both cell-autonomous and non-cell autonomous mechanisms in PCa i<jats:italic>n vitro<\/jats:italic> and in <jats:italic>vivo<\/jats:italic> models and suggest its potential as a therapeutic target in a subset of PCa.<\/jats:p>","DOI":"10.1186\/s12967-025-06540-0","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T10:29:11Z","timestamp":1747650551000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The human RNASET2 alarmin-like molecule differentially affects prostate cancer cells behavior in both cell autonomous and non-cell autonomous manners"],"prefix":"10.1186","volume":"23","author":[{"given":"Rossella","family":"Roncoroni","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denisa","family":"Baci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Cucchiara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annarosaria","family":"de Vito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Gallazzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Teresa","family":"Palano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Olmeo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristian","family":"Rubuano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Giannatiempo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Monti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaella","family":"Bombelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniele","family":"Mercatelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanna","family":"Finzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Franzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"La Rosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas M.","family":"Noonan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Bassani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Mortara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4790-0861","authenticated-orcid":false,"given":"Antonino","family":"Bruno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Acquati","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,19]]},"reference":[{"key":"6540_CR1","first-page":"7","volume":"72","author":"RL Siegel","year":"2022","unstructured":"Siegel RL, Miller KD, Fuchs HE, Jemal A. 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