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ZBP1 驱动头颈部鳞状细胞癌中 CD8+ T 细胞介导的抗肿瘤免疫

英文原题：ZBP1 Drives CD8+ T cell-mediated anti-tumor immunity in head and neck squamous cell carcinoma.

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ZBP1 Drives CD8+ T cell-mediated anti-tumor immunity in head and neck squamous cell carcinoma.

PubMed 2026/05/26（内容时间） PLoS Genet Q2 · IF 3.9（JCR 2025）

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头颈部鳞癌地区：中国
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中文摘要

头颈部鳞状细胞癌（HNSCC）由于免疫“冷”肿瘤微环境（TME），常对PD-1阻断产生耐药。在此，我们确定Z-DNA结合蛋白1（ZBP1）是重编程免疫抑制性TME的关键免疫调节因子。整合TCGA/SangerBox分析显示，ZBP1是一个枢纽基因，与细胞毒性CD8+ T细胞（r = 0.48，p < 0.0001）和M1巨噬细胞（r = 0.39，p < 0.0001）强相关。在92例HNSCC标本中的多模型验证显示，与正常组织相比，ZBP1表达升高（p < 0.01），并通过多重免疫荧光显示其与浸润的CD8+/CD4+ T细胞和CD68+巨噬细胞共定位。

临床上，高ZBP1预示生存改善（总生存期HR = 0.61；疾病特异性生存HR = 0.45；p < 0.0001）和早期分期表现（p = 0.004）。在机制上，SCC-7/MOC2模型中ZBP1过表达抑制肿瘤生长，同时增强IFN-γ+ CD8+ T细胞活化并减少M2极化（CD206+：ZBP1高表达组为16.91%，对照组为38.19%，p < 0.001）。单细胞转录组学揭示，ZBP1通过趋化因子信号网络驱动TME重塑，并扩增效应T细胞区室，流式细胞术验证CD8+ T细胞浸润增加1.49倍。空间分析显示，ZBP1过表达放大了免疫细胞串扰（相互作用增加1.65倍，p < 0.001），上调CD8+ T细胞趋化（CXCR3/CCR5-CCL5轴）和效应功能（p < 0.0001）。

同时，它通过代谢重编程抑制免疫抑制通路，确立ZBP1作为同步调节淋巴细胞募集和髓系抑制的双重调节因子。我们的整合性方法将计算生物学与功能验证相结合，证明ZBP1能够将“冷”肿瘤转化为免疫活跃的生态位。这项工作将ZBP1定位为检查点抑制剂应答的分层生物标志物，以及HNSCC中TME重编程的治疗靶点。

展开英文摘要原文

Head and neck squamous cell carcinoma (HNSCC) frequently resists PD-1 blockade due to an immunologically "cold" tumor microenvironment (TME).

Here, we identify Z-DNA binding protein 1 (ZBP1) as a key immunoregulator that reprograms immune-suppressive TMEs. Integrated TCGA/SangerBox analyses revealed ZBP1 as a hub gene strongly correlated with cytotoxic CD8+ T cells (r = 0. 48, p < 0. 0001) and M1 macrophages (r = 0. 39, p < 0. 0001).

Multi-model validation in 92 HNSCC specimens revealed elevated ZBP1 expression versus normal tissues (p < 0. 01), co-localized with infiltrating CD8+/CD4+ T cells and CD68+ macrophages through multiplex immunofluorescence. Clinically, high ZBP1 predicted improved survival (HR = 0. 61 for overall survival; HR = 0. 45 for disease specific survival; p < 0. 0001) and early-stage presentation (p = 0. 004).

Mechanistically, ZBP1 overexpression in SCC-7/MOC2 models suppressed tumor growth while enhancing IFN-γ+ CD8+ T cell activation and reducing M2 polarization (CD206+: 16. 91% vs 38. 19% in ZBP1-high vs control, p < 0. 001). Single-cell transcriptomics uncovered ZBP1-driven TME remodeling through chemokine signaling networks and expanded effector T cell compartments, validated by 1. 49-fold increased CD8+ T cell infiltration via flow cytometry.

Spatial analysis revealed ZBP1 overexpression amplified immune cell crosstalk (1. 65-fold interaction increase, p < 0. 001), upregulating CD8+ T cell chemotaxis (CXCR3/CCR5-CCL5 axis) and effector functions (p < 0. 0001). Concurrently, it suppressed immunosuppressive pathways through metabolic reprogramming, establishing ZBP1 as a dual regulator synchronizing lymphocyte recruitment and myeloid suppression.

Our integrative approach bridges computational biology with functional validation, demonstrating ZBP1's capacity to convert "cold" tumors into immunologically active niches. This work positions ZBP1 as both a stratification biomarker for checkpoint inhibitor response and a therapeutic target for TME reprogramming in HNSCC.

论文信息

作者
Min Y、Song G、Yang L、He L、Xu S、Gao K、Liu Z、Peng X
第一作者单位
Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, &#x200c;&#x200c;Chengdu, China.China
通讯作者单位
Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy,&#x200c;&#x200c; West China Hospital, Sichuan University, Chengdu, Sichuan, China.China
期刊
PLoS genetics2026 May
原文标识
PubMed 42189863　·　DOI 10.1371/journal.pgen.1012107

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