{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:52:59Z","timestamp":1793321579214,"version":"4.5.0"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, poses a formidable therapeutic challenge, due to its intrinsic radio- and chemoresistance and its ability to create a hostile, immunosuppressive tumor microenvironment (TME). Drug repurposing has emerged as a promising strategy to fight GBM. In this context, our efforts focused on chlorpromazine (CPZ), a first-generation antipsychotic agent previously shown by us to exert anti-tumor effects in both preclinical and clinical settings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated the role of CPZ in remodeling the GBM microenvironment and shaping immune responses using four GBM cell lines, two standard anchorage-dependent models and two patient-derived neurospheres, enriched for tumoral stem cells. We determined cGAS-STING pathway activation and downstream gene expression via flow cytometry and RT-PCR. The cellular secretome following drug treatment was profiled via a luminescence cytokinome assay using a panel of 27 chemokines. Macrophages were phenotyped by flow cytometry using M1 and\/or M2 specific markers and, finally, PD-L1 expression was assessed by quantitative flow cytometry and immunoblot analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We demonstrate that CPZ, alone or in combination with temozolomide (TMZ), the current standard of care, activates the cGAS-STING signaling pathway, thus promoting anti-tumor immune responses. Importantly, CPZ counteracts the immunosuppressive effects of TMZ, hindering some TMZ-induced processes as: i) induction of tumorigenic cytokines; ii) macrophage polarization toward a tumor-supportive M2-like phenotype, and iii) increase of PD-L1 expression, a key mechanism of immune evasion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study uncovers that CPZ exerts a previously unrecognized anti-cancer immunomodulatory activity, remodeling the immune microenvironment and enhancing the anti-tumor immune response. By overcoming TMZ resistance, CPZ not only exerts a direct anti-neoplastic effect, but also sensitizes GBM cells to standard therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1743232","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T06:33:10Z","timestamp":1771309990000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Chlorpromazine activates cGAS-STING signaling and reprograms the immune response in glioblastoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Giulia","family":"Fanelli","sequence":"first","affiliation":[{"name":"Cellular Networks and Molecular Therapeutic Targets, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) - Regina Elena National Cancer Institute","place":["Rome, 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Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Abbruzzese","sequence":"additional","affiliation":[{"name":"Cellular Networks and Molecular Therapeutic Targets, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) - Regina Elena National Cancer Institute","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.17247","article-title":"Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4\u20131 regulatory 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