{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:07:44Z","timestamp":1792786064043,"version":"4.5.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273482"],"award-info":[{"award-number":["82273482"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81772653"],"award-info":[{"award-number":["81772653"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Postdoctoral Fellowship Program of China Postdoctoral Science Foundation","award":["GZB20250527"],"award-info":[{"award-number":["GZB20250527"]}],"id":[{"id":"https:\/\/ror.org\/0426zh255","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Glioma-associated macrophages (GAMs) promote glioma progression, but the membrane-proximal mechanisms sustaining their tumor-supportive states remain poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Bulk and single-cell transcriptomic analyses, human glioma specimens, GAM models, and orthotopic glioma models were used to define the expression and function of NFAM1. Lipid-raft fractionation, co-immunoprecipitation, proximity ligation, domain-mutant rescue, IP3 and Ca2+ measurements, and NFAT1 nuclear translocation assays delineated its signaling mechanism. Pharmacological, macrophage-depletion\/reconstitution, and inducible genetic models evaluated its therapeutic relevance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NFAM1 was enriched in monocyte-derived, M2-like GAMs and associated with higher glioma grade, IDH-wild-type status, and poor survival. NFAM1 promoted GAM migration and M2-like polarization, thereby enhancing mesenchymal plasticity of glioma stem cells (GSCs), angiogenesis, and glioma progression. Mechanistically, phosphorylated NFAM1 recruited DAPP1 and PLCG2 through ITAM-SH2-dependent interactions within lipid rafts, organizing a spatially coordinated and functionally ordered signaling module. DAPP1 acted upstream of PLCG2 to promote IP3 production, Ca2+ signaling, and NFAT1 nuclear translocation. Madecassoside showed ITAM-dependent cellular target engagement with NFAM1, disrupted this signaling module, suppressed tumor-supportive GAM phenotypes, reduced orthotopic tumor growth, and prolonged survival. Its antitumor activity was markedly diminished after peripheral macrophage depletion or reconstitution with NFAM1-deficient bone marrow-derived macrophages. Moreover, inducible NFAM1 knockdown in reconstituted BMDM-derived GAMs after tumor establishment reduced tumor burden and extended survival.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>NFAM1 spatially organizes lipid-raft-restricted DAPP1-PLCG2-Ca2+-NFAT1 signaling in monocyte-derived GAMs and represents a therapeutically targetable vulnerability in glioma.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/neuonc\/noag240","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:03:59Z","timestamp":1790769839000},"source":"Crossref","is-referenced-by-count":0,"title":["NFAM1 organizes a lipid raft-restricted DAPP1-PLCG2 module to drive M2-like GAM polarization via Ca2+-NFAT1 signaling in glioma"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0606-7965","authenticated-orcid":false,"given":"Yaochuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, The First Hospital of China Medical University , Shenyang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4093-9399","authenticated-orcid":false,"given":"Rongjin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Hospital of China Medical University , Shenyang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifu","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Hospital of China Medical University , Shenyang,","place":["China"]},{"name":"Department of Otolaryngology and Head and Neck Surgery, The First Hospital of China Medical University , 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