癌症相关成纤维细胞在胶质母细胞瘤微环境重塑及治疗抵抗中的作用研究进展

Research Progress on the Role of Cancer-Associated Fibroblasts in Microenvironmental Remodeling and Therapeutic Resistance in Glioblastoma

摘要:

胶质母细胞瘤（glioblastoma，GBM）是成人中枢神经系统最常见、恶性程度最高的原发性脑肿瘤之一，具有浸润性生长、术后易复发和对放化疗及免疫治疗反应有限等特点。近年来，肿瘤微环境在GBM进展和治疗抵抗中的作用受到广泛关注。癌症相关成纤维细胞（cancer-associated fibroblasts，CAFs）及GBM相关CAF样细胞（GBM-associated CAF-like cells）作为GBM微环境中的重要基质成分，可通过分泌细胞因子和生长因子、合成并重塑细胞外基质、调控肿瘤细胞与免疫细胞及血管相关细胞之间的相互作用，参与GBM侵袭、血管生成、免疫抑制及治疗抵抗过程。随着单细胞测序、空间转录组学和多组学技术的发展，GBM相关CAF样细胞的潜在来源、表型异质性和功能状态逐渐被揭示，其与胶质瘤干细胞、肿瘤相关巨噬细胞、小胶质细胞、调节性T细胞及内皮细胞之间的互作网络，可能是推动GBM恶性进展和复发的重要机制。本综述梳理了GBM相关CAF样细胞的起源，阐述其表型可塑性和功能异质性的最新知识，重点探讨其与GBM细胞外基质的相互作用和细胞间串扰，以及当前靶向CAF样细胞的干预策略和未来的发展方向。

Abstract:

Glioblastoma (GBM) is the most common and aggressive primary malignant tumor of the adult central nervous system (CNS). Its diffuse infiltration, high recurrence rate, marked intratumoral heterogeneity, and limited response to radiotherapy, temozolomide-based chemotherapy, targeted therapy, and immunotherapy are closely associated with a complex and immunosuppressive tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), a major stromal component in many solid tumors, and GBM-associated CAF-like cells have recently emerged as important regulators of matrix remodeling and therapeutic resistance in GBM. Although classical fibroblasts are scarce in the CNS, accumulating evidence from cell isolation, transcriptomics, single-cell RNA sequencing, spatial transcriptomics, proteomics, and functional studies indicates that CAF-like cells with stromal-remodeling capacity, protumor functions, and spatial proximity to malignant and vascular niches are present in GBM. These cells may originate from resident or recruited mesenchymal stromal cells, bone marrow-derived mesenchymal stem cells, endothelial cells undergoing endothelial-to-mesenchymal transition, and tumor-activated astrocytes, suggesting substantial cellular plasticity and functional heterogeneity. Their identification requires integrated assessment of pan-CAF markers, GBM-related functional markers, spatial localization, copy-number status, and prognostic candidates rather than reliance on any single marker. This framework may also improve risk stratification and selection of patients for combination therapy. This review summarizes current knowledge regarding the origin, molecular characteristics, biological functions, and therapeutic relevance of CAFs and CAF-like cells in the GBM microenvironment. Particular attention is given to their interactions with extracellular matrix (ECM) components, glioma stem cells (GSCs), endothelial cells, tumor-associated macrophages/microglia, regulatory T cells, and effector T cells. CAF-like cells can secrete collagen, fibronectin, fibroblast activation protein (FAP), matrix metalloproteinases (MMPs), cytokines, chemokines, and growth factors, thereby promoting ECM deposition, matrix stiffness, tumor cell invasion, GSC niche maintenance, and metabolic adaptation. Through osteopontin (OPN)-CD44, hepatocyte growth factor (HGF)-c-MET, collagen type I (COL1)-solute carrier family 1 member 5 (SLC1A5), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), CXCL12/CXCR4, transforming growth factor-β (TGF-β), insulin-like growth factor binding protein 2 (IGFBP2), and LRRC15-interleukin-8 (IL-8) signaling, CAF-like cells contribute to abnormal angiogenesis, macrophage polarization, regulatory T-cell recruitment, CD8+ T-cell dysfunction, immune escape, and resistance to conventional and immune-based therapies. Targeting CAF-like cells may therefore provide a complementary strategy for GBM treatment. Potential approaches include FAP-based positron emission tomography (PET) imaging and radionuclide therapy, FAP-directed chimeric antigen receptor T-cell (CAR-T) therapy, blockade of TGF-β and CXCL12/CXCR4 signaling, LRRC15-targeted combination therapy, and nanoparticle-mediated drug delivery across the blood-brain barrier. However, CAF heterogeneity, overlapping markers, context-dependent functions, limited intracranial drug penetration, and insufficient GBM-specific preclinical models remain major challenges. Future studies should integrate single-cell multi-omics, spatial profiling, organoid models, and humanized systems to define GBM-specific CAF-like subtypes, establish reliable biomarkers, and develop precise CAF-targeted interventions that can be rationally combined with existing GBM therapies.