{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T02:32:53Z","timestamp":1788057173991,"version":"build-2784847793"},"reference-count":142,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"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:p>\n                    Diffuse Midline Glioma (DMG), often formerly called Diffuse Intrinsic Pontine Glioma (DIPG) when in the brainstem, DMG\/DIPG is a lethal pediatric brain tumor defined by infiltrative growth, resistance to conventional therapies, and a profound immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), including resident microglia and infiltrating monocyte-derived macrophages, are the predominant immune population in DMG\/DIPG. These cells adopt an immunosuppressive, pro-tumor state, promoting immune evasion and limiting the efficacy of therapies such as chimeric antigen receptor (CAR) T cells. Reprogramming TAMs toward a pro-inflammatory, anti-tumor phenotype offers a promising strategy to remodel the DMG\/DIPG microenvironment. This review is the first to provide a comprehensive, integrative perspective on TAM-directed strategies in DMG\/DIPG, spanning molecular, epigenetic, and biophysical approaches. We summarize TAM-mediated tumor progression and therapy resistance, and discuss molecular reprogramming strategies, including colony-stimulating factor 1 receptor (CSF1R) inhibition, microRNA-based circuits, and epigenetic modulators such as histone deacetylase (HDAC) and bromodomain and extra-terminal domain (BET) inhibitors. Nanoparticle-mediated delivery systems allow selective TAM targeting and enhanced blood-brain barrier (BBB) penetration. Additional strategies, including oncolytic viruses and macrophage-specific checkpoint blockade (e.g., CD47\/SIRP\u03b1 axis inhibitors), simultaneously promote tumor clearance and immune activation. We also highlight emerging biophysical approaches to modulate TAM function\n                    <jats:italic>in situ<\/jats:italic>\n                    . Photodynamic therapy (PDT) induces immunogenic cell death and pro-inflammatory macrophage activity, while focused ultrasound (FUS) transiently disrupts the BBB to enhance drug delivery and immune infiltration. Photobiomodulation and low-level light therapy (LLLT) may influence macrophage metabolism and phenotype, though their application in DMG\/DIPG remains largely unexplored. Finally, we discuss combinatorial strategies integrating TAM reprogramming with CAR T cell therapy or chemotherapy to overcome the immunologically \u201ccold\u201d nature of DMG\/DIPG. By uniting mechanistic insights with translational opportunities, this review establishes TAM reprogramming as a critical, underexplored frontier in DMG\/DIPG immunotherapy, offering the potential to render an otherwise intractable tumor immunologically targetable.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1788956","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T14:12:12Z","timestamp":1773756732000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Reprogramming tumor-associated macrophages in DMG\/DIPG: emerging molecular and biophysical strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"Khatereh","family":"Khorsandi","sequence":"first","affiliation":[{"name":"Center for Cancer and Immunology Research, Children\u2019s National Hospital","place":["Washington, DC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynne","family":"El Ghorayeb","sequence":"additional","affiliation":[{"name":"Center for Cancer and Immunology Research, Children\u2019s National Hospital","place":["Washington, DC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elton","family":"VanNoy","sequence":"additional","affiliation":[{"name":"Center for Cancer and Immunology Research, Children\u2019s National Hospital","place":["Washington, DC, United States"]},{"name":"The Institute for Biomedical Sciences, The George Washington University","place":["Washington, DC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalia","family":"Haydar","sequence":"additional","affiliation":[{"name":"Center for Cancer and Immunology Research, Children\u2019s National Hospital","place":["Washington, DC, United States"]},{"name":"The Institute for Biomedical Sciences, The George Washington 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