肿瘤细胞治疗研究
英文原题：Reprogramming tumor-associated macrophages in DMG/DIPG: emerging molecular and biophysical strategies.
Reprogramming tumor-associated macrophages in DMG/DIPG: emerging molecular and biophysical strategies.
弥漫性中线胶质瘤（DMG），当位于脑干时通常曾被称为弥漫性内生性桥脑胶质瘤（DIPG），DMG/DIPG是一种致死性儿童脑肿瘤，其特征为浸润性生长、对常规治疗耐药以及深度免疫抑制的肿瘤微环境（TME）。
弥漫性中线胶质瘤（DMG），当位于脑干时通常曾被称为弥漫性内生性桥脑胶质瘤（DIPG），DMG/DIPG是一种致死性儿童脑肿瘤，其特征为浸润性生长、对常规治疗耐药以及深度免疫抑制性肿瘤微环境（TME）。肿瘤相关巨噬细胞（TAM），包括驻留小胶质细胞和浸润性单核细胞来源巨噬细胞，是DMG/DIPG中占主导地位的免疫细胞群。这些细胞呈现免疫抑制性、促肿瘤状态，促进免疫逃逸并限制嵌合抗原受体（CAR）T细胞等疗法的疗效。将TAM重编程为促炎、抗肿瘤表型为重塑DMG/DIPG微环境提供了一种有前景的策略。本综述首次对DMG/DIPG中靶向TAM的策略提供了全面、整合性的视角，涵盖分子、表观遗传和生物物理方法。我们总结了TAM介导的肿瘤进展和治疗耐药，并讨论了分子重编程策略，包括集落刺激因子1受体（CSF1R）抑制、基于microRNA的回路以及表观遗传调节剂如组蛋白去乙酰化酶（HDAC）和溴结构域及超末端结构域（BET）抑制剂。纳米颗粒介导的递送系统允许选择性靶向TAM并增强血脑屏障（BBB）穿透。其他策略，包括溶瘤病毒和巨噬细胞特异性检查点阻断（例如CD47/SIRP轴抑制剂），同时促进肿瘤清除和免疫激活。我们还重点介绍了在原位调节TAM功能的新兴生物物理方法。光动力疗法（PDT）可诱导免疫原性细胞死亡和促炎性巨噬细胞活性，而聚焦超声（FUS）可短暂破坏BBB以增强药物递送和免疫浸润。光生物调节和低强度光疗法（LLLT）可能影响巨噬细胞代谢和表型，尽管其在DMG/DIPG中的应用在很大程度上尚未被探索。最后，我们讨论了将TAM重编程与CAR T细胞疗法或化疗相结合的联合策略，以克服DMG/DIPG免疫“冷”的特性。通过将机制见解与转化机会相结合，本综述确立了TAM重编程作为DMG/DIPG免疫治疗中一个关键且尚未被充分探索的前沿领域，为原本难以治疗的肿瘤提供了免疫靶向的可能性。
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 axis inhibitors), simultaneously promote tumor clearance and immune activation. We also highlight emerging biophysical approaches to modulate TAM function in situ . 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 "cold" 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.
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