Ren Yubo, Lu Dengfeng, Wang Fei, Wang Zixuan, Li Jinfeng, Huang Run, Lu Yue, Duan Aojie, Shou Renjie, Liu Jiangang, Chen Zhouqing, Wang Zhong, Sun Xiaoou
Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China.
PLoS One. 2025 Aug 11;20(8):e0329801. doi: 10.1371/journal.pone.0329801. eCollection 2025.
Cancer-associated fibroblasts (CAFs) are a critical component of the glioma microenvi-ronment and play essential roles in tumor progression and resistance to immunotherapy. To comprehensively characterize CAF heterogeneity and their interactions with immune cells, we conducted an integrative multi-omics analysis incorporating single-cell and bulk RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence. This approach identified nine distinct CAF subtypes with phenotypic and functional diversity, including tumor-like CAFs (tCAFs), myofibroblast-like CAFs (myCAFs), vascular CAFs (vCAFs), metabolic CAFs (meCAFs), proliferative CAFs (pCAFs), antigen-presenting CAFs (apCAFs), interferon-responsive CAFs (infCAFs), inflammatory CAFs (iCAFs), and a group of CAFs with unknown identity. Several subtypes were significantly associated with poor clinical outcomes. Notably, apCAFs engaged in extensive crosstalk with M2-polarized macrophages via TGF-β signaling pathways. Spatial transcriptomic pro-filing and immunofluorescence imaging revealed the co-localization of apCAFs and M2 macrophages at the tumor periphery, indicating the formation of an immunosuppressive niche. Moreover, AQP4 was identified as a specific marker of apCAFs, and its expression was significantly correlated with poor prognosis and resistance to immunotherapy. These findings offer a comprehensive atlas of CAF heterogeneity in glioma and highlight the therapeutic promise of targeting apCAF-M2 macrophage interactions or AQP4 to over-come immune resistance and improve clinical outcomes.
癌症相关成纤维细胞（CAFs）是胶质瘤微环境的关键组成部分，在肿瘤进展和免疫治疗耐药中发挥重要作用。为全面表征CAF的异质性及其与免疫细胞的相互作用，我们进行了一项整合多组学分析，纳入了单细胞和批量RNA测序、空间转录组学以及多重免疫荧光。该方法鉴定出九种具有表型和功能多样性的不同CAF亚型，包括肿瘤样CAFs（tCAFs）、肌成纤维细胞样CAFs（myCAFs）、血管CAFs（vCAFs）、代谢CAFs（meCAFs）、增殖性CAFs（pCAFs）、抗原呈递CAFs（apCAFs）、干扰素应答性CAFs（infCAFs）、炎性CAFs（iCAFs）以及一组身份不明的CAFs。几种亚型与不良临床结局显著相关。值得注意的是，apCAFs通过TGF-β信号通路与M2极化巨噬细胞进行广泛的串扰。空间转录组分析和免疫荧光成像显示apCAFs和M2巨噬细胞在肿瘤周边共定位，表明形成了免疫抑制微环境。此外，水通道蛋白4（AQP4）被鉴定为apCAFs的特异性标志物，其表达与不良预后和免疫治疗耐药显著相关。这些发现提供了胶质瘤中CAF异质性的全面图谱，并突出了靶向apCAF-M2巨噬细胞相互作用或AQP4以克服免疫耐药并改善临床结局的治疗前景。
