Background: Tumor-associated macrophages (TAMs) are essential regulators of the glioblastoma (GBM) microenvironment; their functional heterogeneity and interaction networks are not fully elucidated. We identifyRNF135as a novel TAM-enriched gene associated with immune activation and adverse prognosis in GBM. Methods: To evaluateRNF135’s expression profile, prognostic significance, and functional pathways, extensive transcriptome analyses from TCGA and CGGA cohorts were conducted. The immunological landscape and cellular origin ofRNF135were outlined using single-cell RNA-seq analyses and bulk RNA-seq immune deconvolution (MCP-counter, xCell and ssGSEA). Cell–cell communication networks between tumor cells andRNF135-positive and -negative tumor-associated macrophage subsets were mapped using CellChat. Results:RNF135predicted a poor overall survival and was markedly upregulated in GBM tissues. Functional enrichment analyses showed that increased cytokine signaling, interferon response, and innate immune activation were characteristics ofRNF135-high samples. Immune infiltration profiling showed a strong correlation between the abundance of T cells and macrophages andRNF135expression. According to the single-cell analyses,RNF135was primarily expressed in TAMs, specifically in proliferation, phagocytic, and transitional subtypes.RNF135-positive TAMs demonstrated significantly improved intercellular communication with aggressive tumor subtypes in comparison toRNF135-negative TAMs. This was facilitated by upregulated signaling pathways such as MHC-II, CD39, ApoE, and most notably, the CCL signaling axis. The CCL3/CCL3L3–CCR1 ligand–receptor pair was identified as a major mechanistic driver of TAM–TAM crosstalk. HighRNF135expression was also linked to greater sensitivity to Selumetinib, a selective MEK1/2 inhibitor that targets the MAPK/ERK pathway, according to drug sensitivity analysis. Conclusions:RNF135defines a TAM phenotype in GBM that is both immunologically active and immunosuppressive. This phenotype promotes inflammatory signaling and communication between cells in the tumor microenvironment. Targeting the CCL–CCR1 axis or combiningRNF135-guided immunomodulation with certain inhibitors could be a promising therapeutic strategies for GBM.
背景：肿瘤相关巨噬细胞（TAMs）是胶质母细胞瘤（GBM）微环境的关键调节因子，其功能异质性及相互作用网络尚未完全阐明。本研究鉴定出RNF135作为GBM中一种新型TAM富集基因，与免疫激活及不良预后相关。方法：通过TCGA和CGGA队列的转录组分析，系统评估RNF135的表达特征、预后意义及功能通路。结合单细胞RNA测序分析和批量RNA测序免疫反卷积技术（MCP-counter、xCell和ssGSEA），解析RNF135的免疫学特征及细胞来源。利用CellChat工具绘制肿瘤细胞与RNF135阳性/阴性TAM亚群间的细胞间通讯网络。结果：RNF135高表达预示GBM患者总生存期缩短，且在GBM组织中显著上调。功能富集分析显示，RNF135高表达样本呈现细胞因子信号增强、干扰素反应及天然免疫激活特征。免疫浸润分析表明T细胞与巨噬细胞丰度与RNF135表达呈强相关。单细胞分析揭示RNF135主要表达于TAMs，尤其富集于增殖型、吞噬型和过渡型亚群。与RNF135阴性TAMs相比，RNF135阳性TAMs与侵袭性肿瘤亚型间的细胞通讯显著增强，其机制涉及MHC-II、CD39、ApoE及尤为关键的CCL信号轴等通路上调。其中CCL3/CCL3L3–CCR1配体-受体对被确定为TAM-TAM互作的核心驱动机制。药物敏感性分析显示，RNF135高表达与MAPK/ERK通路靶向药物司美替尼（Selumetinib）的敏感性增强相关。结论：RNF135在GBM中界定了一种兼具免疫活性与免疫抑制特性的TAM表型，该表型通过促进肿瘤微环境中的炎症信号传导与细胞间通讯驱动肿瘤进展。靶向CCL–CCR1信号轴或联合RNF135引导的免疫调节与特定抑制剂，可能成为GBM的潜在治疗策略。
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