{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T05:14:39Z","timestamp":1778130879559,"version":"3.51.4"},"reference-count":22,"publisher":"Frontiers Media SA","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\/"}],"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>Osteosarcoma (OS) is a common primary malignant bone tumor in children and adolescents. Increasing evidence suggests that immune dysregulation contributes to OS progression, but its tissue-level and systemic features remain incompletely defined. This study aimed to characterize immune-related alterations in OS and identify key immunoregulatory molecules associated with disease progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Public transcriptomic datasets from the Gene Expression Omnibus (GSE14359, GSE19276, GSE21257, GSE28424, and GSE36001) were analyzed using differential expression, functional enrichment, protein\u2013protein interaction analysis, immune-infiltration analysis, and machine-learning algorithms. Public single-cell RNA-seq data from six primary OS samples were additionally analyzed to define the cellular composition of the OS microenvironment and localize APOE expression. Peripheral blood parameters were retrospectively compared between 604 OS patients and 600 hospital-based non-malignant controls with cervical spondylosis. APOE expression was further evaluated by immunohistochemistry in paired tumor and adjacent non-tumor tissues.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Five core genes were identified, including APOE, CD74, RPL26L1, WDR12, and CXCL12, among which APOE was significantly downregulated in OS tissues. Immune-infiltration analysis suggested reduced neutrophils and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells with enrichment of M2 macrophages, consistent with an immunosuppressive microenvironment. Single-cell RNA-seq analysis of 22,997 cells identified 11 major cell populations, with macrophages and fibroblasts as prominent components. APOE expression was predominantly enriched in macrophages, with lower expression in fibroblasts and mesenchymal stem cells. In the peripheral blood analysis, OS patients showed altered neutrophil-related indices, characterized by lower absolute neutrophil counts but higher neutrophil percentages than controls. Immunohistochemistry further supported reduced APOE expression in OS tissues.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study integrates tissue-level, single-cell, and exploratory peripheral hematologic evidence to support immune-related alterations in OS. APOE downregulation and altered peripheral neutrophil-related indices may represent clinically relevant features associated with immune dysregulation in osteosarcoma.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1753859","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:55:52Z","timestamp":1778129752000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical and tissue evidence of immune dysregulation in osteosarcoma: altered peripheral neutrophil-related indices and reduced APOE expression"],"prefix":"10.3389","volume":"17","author":[{"given":"Jichong","family":"Zhu","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Guangxi Medical University","place":["Nanning, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengqian","family":"Huang","sequence":"additional","affiliation":[{"name":"The Affiliated Hospital of Youjiang Medical University for Nationalities","place":["Baise, China"]},{"name":"Key Laboratory of Molecular Pathology in Tumors of Guangxi Higher Education Institutions","place":["Baise, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiming","family":"Tan","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Guangxi Medical University","place":["Nanning, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-021-00519-8","article-title":"Advancing therapy for osteosarcoma","volume":"18","author":"Gill","year":"2021","journal-title":"Nat Rev Clin Oncol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1186\/s12943-024-02105-9","article-title":"Advances on immunotherapy for osteosarcoma","volume":"23","author":"Yu","year":"2024","journal-title":"Mol 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