Li Xuetong, Gao Wei, Long Xinmiao, Wu Minghua
The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, China.
The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, China.
Research (Wash D C). 2025 Aug 12;8:0836. doi: 10.34133/research.0836. eCollection 2025.
Glioblastoma (GBM) is a highly aggressive brain tumor characterized by an immunosuppressive microenvironment that importantly contributes to treatment resistance. Monocyte-derived macrophages (MDMs), which comprise approximately 50% of the cellular population within the GBM microenvironment, represent a major subset of tumor-associated macrophages. These cells drive tumor progression by promoting angiogenesis, immune evasion, and the phenotypic transformation of tumor cells. MDM infiltration is mediated by specific signaling pathways and regulated by the disruption of the blood-brain barrier and tumor-associated hypoxia. Recent technological advances have uncovered substantial heterogeneity among macrophages, including hypoxia-induced, lipid-metabolizing, phagocytic, and interferon-activated subtypes. This functional diversity is shaped by tumor-specific genetic alterations and metabolic reprogramming. Therapeutic approaches focusing on MDMs include inhibiting their recruitment, enhancing phagocytic activity, employing genetically engineered macrophage, and modulating metabolic pathways. While preclinical studies suggest that these approaches may improve efficacy when combined with immune checkpoint inhibitors, the dynamic spatiotemporal heterogeneity and adaptability of macrophages within the tumor microenvironment remain substantial therapeutic challenges. Future development in combination therapies, integrating single-cell multi-omics, spatial metabolic profiling, and targeted interventions, will be critical to precisely modulate MDMs, overcome immune tolerance, and improve patient outcomes.
胶质母细胞瘤（GBM）是一种高度侵袭性的脑肿瘤，其特征在于免疫抑制微环境，这对治疗抗性有重要影响。单核细胞衍生的巨噬细胞（MDM）约占GBM微环境中细胞群体的50%，是肿瘤相关巨噬细胞的主要亚群。这些细胞通过促进血管生成、免疫逃逸和肿瘤细胞的表型转化来驱动肿瘤进展。MDM浸润由特定信号通路介导，并受血脑屏障破坏和肿瘤相关缺氧的调节。最近的技术进步揭示了巨噬细胞之间存在大量异质性，包括缺氧诱导型、脂质代谢型、吞噬型和干扰素激活型亚型。这种功能多样性由肿瘤特异性基因改变和代谢重编程塑造。针对MDM的治疗方法包括抑制其募集、增强吞噬活性、采用基因工程巨噬细胞以及调节代谢途径。虽然临床前研究表明，这些方法与免疫检查点抑制剂联合使用时可能会提高疗效，但肿瘤微环境中巨噬细胞的动态时空异质性和适应性仍然是重大的治疗挑战。联合疗法的未来发展，整合单细胞多组学、空间代谢谱分析和靶向干预，对于精确调节MDM、克服免疫耐受和改善患者预后至关重要。
