{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T05:07:23Z","timestamp":1778821643336,"version":"3.51.4"},"reference-count":92,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Accion Estrat\u00e9gica en Salud Intramural (AESI) del Instituto de Salud Carlos III","award":["AESI PI21CIII\/00022"],"award-info":[{"award-number":["AESI PI21CIII\/00022"]}]},{"name":"Accion Estrat\u00e9gica en Salud Intramural (AESI) del Instituto de Salud Carlos III","award":["PI23CIII\/00057"],"award-info":[{"award-number":["PI23CIII\/00057"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Phosphatidylinositol-3-kinases (PI3Ks) are heterodimers of catalytic and regulatory subunits that regulate cell metabolism, activation, and survival. PI3K, particularly the p110\u03b1 catalytic isoform, is frequently mutated in cancer, and highly specific inhibitors such as alpelisib are currently used in oncology and in PIK3CA-related overgrowth disorders. Given the relevance of macrophages in anti-tumor immunity, we examined the impact of alpelisib on murine monocytes\u2019 intracellular signaling and on in vitro differentiation, polarization, and effector functions of macrophages. Real-time qPCR (RT-qPCR) showed comparable relative expression of PI3K isoforms (p110\u03b1, p110\u03b2, p110\u03b4, p110\u03b3 and p85) in bone marrow monocytes and in macrophages differentiated with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). However, alpelisib increased p110\u03b1, p110\u03b2, and p85 relative gene expression (2\u20133-fold) during M-CSF-dependent differentiation. Functionally, alpelisib-treated M-CSF macrophages displayed enhanced interleukin (IL)-6 and tumor necrosis factor alpha (TNF-\u03b1) secretion and reduced IL-10 production after lipopolysaccharide (LPS) plus interferon gamma (IFN-\u03b3) or LPS stimulation. In contrast, GM-CSF macrophages differentiated with alpelisib secreted lower levels of IL-6 and TNF-\u03b1 and reduced inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1) gene expression. Additionally, cytokine profiles (IL-2, IL-6, IFN-\u03b3 and IL-10) were altered when alpelisib-treated macrophages were cocultured with CD4+ T cells under either antigen-specific or polyclonal activation conditions, indicating that the inhibitor modifies both differentiation and subsequent effector interactions of the macrophages. Thus, alpelisib induces lasting effects on macrophage differentiation and function, with potential implications in tumor-associated macrophages that develop under M-CSF or GM-CSF-rich cancer microenvironments.<\/jats:p>","DOI":"10.3390\/ijms27104171","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T19:10:52Z","timestamp":1778267452000},"page":"4171","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effect of PI3K-p110\u03b1 Inhibitor Alpelisib in the Differentiation and Effector Functions of M-CSF and GM-CSF Macrophages"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7520-1603","authenticated-orcid":false,"given":"Cristina","family":"Villa-G\u00f3mez","sequence":"first","affiliation":[{"name":"Immunology Department, National Centre for Microbiology (CNM), Carlos III Health Institute (ISCIII), 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ver\u00f3nica","family":"Bermejo","sequence":"additional","affiliation":[{"name":"Immunology Department, National Centre for Microbiology (CNM), Carlos III Health Institute (ISCIII), 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inmaculada","family":"M\u00e1rquez-Leiva","sequence":"additional","affiliation":[{"name":"Immunology Department, National Centre for Microbiology (CNM), Carlos III Health Institute (ISCIII), 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9060-9228","authenticated-orcid":false,"given":"Jana","family":"Baranda","sequence":"additional","affiliation":[{"name":"Immunology Department, National Centre for Microbiology (CNM), Carlos III Health Institute (ISCIII), 28220 Madrid, Spain"},{"name":"Microbiology Section, Department of Pharmaceutical and Health Sciences, Faculty of Pharmacy, San Pablo-CEU University, 28668 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4016-1848","authenticated-orcid":false,"given":"Alejandro C.","family":"Briones","sequence":"additional","affiliation":[{"name":"Immunology Department, National Centre for Microbiology (CNM), Carlos III Health Institute (ISCIII), 28220 Madrid, Spain"},{"name":"Department of Immunology, Complutense University School of Medicine, i+12 Research Institute, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Cervera","sequence":"additional","affiliation":[{"name":"Immunology Department, National Centre for Microbiology (CNM), Carlos III Health Institute (ISCIII), 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordi","family":"Ochando","sequence":"additional","affiliation":[{"name":"Immunology Department, National Centre for Microbiology (CNM), Carlos III Health Institute (ISCIII), 28220 Madrid, Spain"},{"name":"Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9032-0072","authenticated-orcid":false,"given":"Jos\u00e9 Mar\u00eda","family":"Rojo","sequence":"additional","affiliation":[{"name":"Margarita Salas Center for Biological Research (CIB), Spanish National Research Council (CSIC), 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6973-0835","authenticated-orcid":false,"given":"Pilar","family":"Portol\u00e9s","sequence":"additional","affiliation":[{"name":"Immunology Department, National Centre for Microbiology (CNM), Carlos III Health Institute (ISCIII), 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/s41392-021-00828-5","article-title":"Targeting PI3K\/Akt signal transduction for cancer therapy","volume":"6","author":"He","year":"2021","journal-title":"Signal Transduct. 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