头颈部肿瘤中的癌症相关成纤维细胞：信号网络及治疗意义——来自前庭神经鞘瘤的启示

文献信息

中文摘要

背景： 癌症相关成纤维细胞（CAFs）是异质性基质细胞，影响头颈部鳞状细胞癌（HNSCC）中的细胞外基质（ECM）组织、肿瘤细胞状态、免疫和治疗反应。本综述综合了关于CAF起源和状态的证据，以及介导成纤维细胞与肿瘤和免疫细胞相互作用的转化生长因子β（TGF-β）、Wnt/β-catenin、PI3K/AKT/mTOR和Hippo-YAP/TAZ网络的证据。前庭神经鞘瘤（VS）仅被视为一个产生假设的良性基质参考：两种肿瘤均包含成纤维细胞和ECM重塑区室，但在起源细胞、解剖结构、致癌驱动因素、免疫背景和侵袭行为方面存在根本差异。除非研究明确应用了该术语，否则VS基质成纤维细胞不被指定为CAFs，跨肿瘤观察也不被视为生物学等同性的证据。单细胞和空间研究揭示了多种HNSCC成纤维细胞状态，包括肌成纤维细胞、炎症性、抗原呈递性和成纤维细胞网状细胞（FRC）样以及免疫调节性群体，但命名和标志物集仍不一致，大多数推断的功能需要扰动验证。转化证据同样不均衡：广泛的CAF耗竭在某些非HNSCC模型中可能有害，而通路或状态选择性调节主要得到临床前研究的支持。早期HNSCC试验中的TGF-β/程序性死亡配体1（PD-L1）阻断和NADPH氧化酶1/4（NOX1/4）抑制提供了可行性信号，但未提供明确疗效。当前证据支持对功能定义的CAF状态进行生物标志物引导的研究；VS中的基质观察仍产生假设，需要直接实验验证。

英文摘要

Cancer-associated fibroblasts (CAFs) are heterogeneous stromal cells that influence extracellular matrix (ECM) organisation, tumour-cell state, immunity, and treatment response in head and neck squamous cell carcinoma (HNSCC). This review synthesises evidence on CAF origins and states and on the transforming growth factor beta (TGF-β), Wnt/β-catenin, PI3K/AKT/mTOR, and Hippo-YAP/TAZ networks that mediate fibroblast interactions with tumour and immune cells. Vestibular schwannoma (VS) is considered only as a hypothesis-generating benign stromal reference: both tumours contain fibroblast and ECM-remodelling compartments, but differ fundamentally in cell of origin, anatomy, oncogenic drivers, immune context, and invasive behaviour. VS stromal fibroblasts are not designated as CAFs unless a study has explicitly applied that term, and cross-tumour observations are not treated as evidence of biological equivalence. Single-cell and spatial studies reveal multiple HNSCC fibroblast states, including myofibroblastic, inflammatory, antigen-presenting and fibroblastic reticular cell (FRC)-like, and immune-regulatory populations, but nomenclature and marker sets remain inconsistent and most inferred functions require perturbational validation. Translational evidence is similarly uneven: broad CAF depletion can be harmful in some non-HNSCC models, whereas pathway- or state-selective modulation is supported mainly by preclinical studies. Early HNSCC trials of TGF-β/programmed death-ligand 1 (PD-L1) blockade and NADPH oxidase 1/4 (NOX1/4) inhibition provide feasibility signals but not definitive efficacy. Current evidence supports biomarker-guided investigation of functionally defined CAF states; stromal observations in VS remain hypothesis-generating and require direct experimental validation.