喉鳞状细胞癌中免疫启动失败的检验：直接证据、未解关联及区室解析框架

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中文摘要

背景： 喉鳞状细胞癌（LSCC）中持续性免疫启动缺陷的直接证据仍不完整。因此，本综述不将启动失败视为已确立的LSCC机制。相反，它将直接的LSCC观察结果与来自混合部位头颈部鳞状细胞癌队列的证据以及其他肿瘤的机制研究分开，利用这种层级结构来识别有支持的通路节点和未解决的关联。
方法： 直接的LSCC研究支持MHC I类抗原加工组分的反复缺失、肿瘤HLA-DR与临床结果之间的有利关联、PD-L2阳性浆细胞样树突状细胞的积累、树突状细胞状态的重塑，以及肿瘤细胞STING丰度与晚期疾病之间的关联。这些发现均未证明抗原特异性启动。跨肿瘤证据为cDC1交叉呈递、CCR7依赖性迁移、肿瘤引流淋巴结启动以及功能性cGAS-STING信号传导提供了机制背景，但这些关联需要LSCC特异性验证。因此，我们区分MHC I类与MHC II类呈递、交叉呈递与肿瘤细胞HLA-DR表达、淋巴结启动与瘤内再刺激，以及STING丰度与激活、下游输出和功能。
结果： 转化优先事项根据LSCC证据强度和干预可行性被分为基于证据的层级。MHC-I抗原加工机制、PD-L2阳性pDC状态和功能性cGAS-STING能力值得最早进行LSCC特异性验证，而CLEC9A、XCR1和FLT3L导向的cDC1策略在机制上仍具说服力，但主要依赖其他肿瘤系统的证据。未来的多中心研究应纳入HLA基因型、人群多样性、配对的肿瘤和引流淋巴结采样、功能测定以及生物信息学或人工智能整合与外部验证。
结论： 所提出的感知低下、呈递缺陷、调节性DC主导以及信号存在但功能脱节的表型仍是研究构想，而非临床选择工具。该框架旨在检验启动在何处失败（如果确实失败的话），而不将未经证实的LSCC特异性通路作为已确立的生物学呈现。

英文摘要

Direct evidence for a continuous immune-priming defect in laryngeal squamous cell carcinoma (LSCC) remains incomplete. This Review therefore does not treat failed priming as an established LSCC mechanism. Instead, it separates direct LSCC observations from evidence derived from mixed-site head and neck squamous cell carcinoma cohorts and mechanistic studies in other tumors, using this hierarchy to identify supported pathway nodes and unresolved connections. Direct LSCC studies support recurrent loss of MHC class I antigen-processing components, favorable associations between tumor HLA-DR and clinical outcome, accumulation of PD-L2-positive plasmacytoid dendritic cells, remodeling of dendritic cell states, and an association between tumor-cell STING abundance and advanced disease. None of these findings demonstrates antigen-specific priming. Cross-tumor evidence provides mechanistic context for cDC1 cross-presentation, CCR7-dependent migration, tumor-draining lymph-node priming, and functional cGAS-STING signaling, but these links require LSCC-specific validation. We therefore distinguish MHC class I from MHC class II presentation, cross-presentation from tumor-cell HLA-DR expression, lymph-node priming from intratumoral restimulation, and STING abundance from activation, downstream output, and function. Translational priorities are grouped into evidence-based tiers according to the strength of LSCC evidence and intervention tractability. The MHC-I antigen-processing machinery, PD-L2-positive pDC states, and functional cGAS-STING competence merit the earliest LSCC-specific validation, whereas CLEC9A-, XCR1-, and FLT3L-directed cDC1 strategies remain mechanistically compelling but rely mainly on evidence from other tumor systems. Future multicenter studies should incorporate HLA genotype, population diversity, paired tumor and draining-node sampling, functional assays, and bioinformatic or artificial-intelligence integration with external validation. The proposed sensing-low, presentation-deficient, regulatory-DC-dominant, and signal-present but functionally disconnected phenotypes remain research constructs rather than clinical selection tools. The framework is intended to test where priming fails, if it fails at all, without presenting an unproven LSCC-specific pathway as established biology.