Liu Ziyuan, Yang Yufan, Fang Haiting, Cen Bohong, Fan Yiqi, Li Jianlong, Wang Lijie, He Shuai
Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China; National Medical Products Administration Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China.
National Medical Products Administration Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China; Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
Int J Biol Macromol. 2025 May;308(Pt 3):142415. doi: 10.1016/j.ijbiomac.2025.142415. Epub 2025 Mar 22.
Therapeutic strategies aiming at the tumor immune microenvironment (TIME) hold promise for glioblastoma (GBM) treatment. However, adjuvant immunotherapies targeting checkpoint inhibitors just prove effective for a selected group of GBM patients. The extensive involvement of GBM-associated macrophages highlights their potential role in tumor behavior. In-depth exploration of the impact of macrophages on the efficacy of immunotherapy is crucial for enhancing treatment outcomes. In this study, we conducted a comprehensive analysis using bulk RNA-seq, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics to explore the heterogeneity of tumor-associated macrophages (TAMs) in GBM. Flow cytometry was employed to investigate the effects of VSIG4 on TAM phenotypes, and co-culture cellular assays were performed to evaluate its contribution to GBM malignancy. Integrating 16 patient samples, we examined the immunological significance of VSIG4S100A10TAMs. VSIG4 expression on macrophages is significantly upregulated and correlated with the TIME, promoting the polarization of macrophages towards M2 and facilitating GBM progression. Spatial transcriptomics and human samples multiplex immunofluorescence (mIF) confirmed the co-localization of VSIG4S100A10TAMs with various T cells, resulting in the inhibition of T cell immune responses and a reduction in anti-tumor immunity. Our findings demonstrate for the first time that VSIG4S100A10TAM is an independent prognostic indicator of poor outcome for GBM and markedly accumulates in patients exhibiting non-responsiveness to anti-PD-1 immunotherapy. Targeting this specific bifunctional subgroup can potentially open up new avenues for the immunotherapy of GBM.
针对肿瘤免疫微环境（TIME）的治疗策略有望用于胶质母细胞瘤（GBM）的治疗。然而，靶向检查点抑制剂的辅助免疫疗法仅对部分GBM患者有效。GBM相关巨噬细胞的广泛参与突显了它们在肿瘤行为中的潜在作用。深入探究巨噬细胞对免疫治疗疗效的影响对于提高治疗效果至关重要。在本研究中，我们使用批量RNA测序、单细胞RNA测序（scRNA-seq）和空间转录组学进行了全面分析，以探索GBM中肿瘤相关巨噬细胞（TAM）的异质性。采用流式细胞术研究VSIG4对TAM表型的影响，并进行共培养细胞试验以评估其对GBM恶性程度的作用。整合16例患者样本，我们研究了VSIG4⁺S100A10⁺ TAM的免疫学意义。巨噬细胞上VSIG4的表达显著上调且与TIME相关，促进巨噬细胞向M2极化并促进GBM进展。空间转录组学和人体样本多重免疫荧光（mIF）证实VSIG4⁺S100A10⁺ TAM与各种T细胞共定位，导致T细胞免疫反应受到抑制，抗肿瘤免疫力降低。我们的研究结果首次表明，VSIG4⁺S100A10⁺ TAM是GBM预后不良的独立预测指标，并且在对抗PD-1免疫治疗无反应的患者中明显积聚。靶向这一特定的双功能亚群可能为GBM的免疫治疗开辟新途径。
