肿瘤细胞治疗研究
英文原题：Personalised immunotherapy strategies informed by single cell profiling in thyroid cancer: a mini review.
早期仑伐替尼-帕博利珠单抗或塞尔帕替尼-纳武利尤单抗试验显示 ~40% ORR，但 3 级高血压 >60%，促使采用错开起始设计。
甲状腺癌（TC）目前是增长最快的实体瘤之一，但低分化型、未分化型和髓样型治疗进展有限，中位生存期以月计。免疫治疗过去主要由组织学和单基因检测指导，如今正被单细胞分析重塑；单细胞分析揭示了决定治疗应答和耐药的细胞镶嵌特征。对超过15万个肿瘤和免疫细胞转录组的分析发现，肿瘤内存在滤泡样、部分EMT样及去分化甲状腺细胞状态，嵌入“热”型（CD8高、IFN-γ高）、“冷”型（CD8低）及“排斥”型（由基质构成屏障）的免疫生态位。这些表型与PD-1/LAG-3表达、巨噬细胞极化和放射性碘难治相关。功能研究显示，SPP1-CD44和GAS6-AXL相互作用促成上皮-间质转化，而VSIG4+巨噬细胞削弱细胞毒性T细胞活性，共同导致免疫检查点阻断疗效下降。空间转录组进一步证实这些发现，显示PD-L1高表达肿瘤细胞岛与富含CXCL13的三级淋巴结构相距数毫米；CITE-seq则量化患者活检中的可靶向免疫检查点和细胞因子受体。新兴疗法体现了这种精细化认识：PD-1联合LAG-3抑制、靶向CSF-1R的巨噬细胞重编程，以及靶向促甲状腺激素受体的CAR-T细胞疗法正在进入早期临床试验；离体单细胞药物反应分析可使药物组合与个体肿瘤生态系统相匹配。lenvatinib-pembrolizumab或selpercatinib-nivolumab早期试验显示ORR约40%，但3级高血压超过60%，因此采用分阶段起始给药设计。这些进展提高了发病机制解析精度，优化了患者筛选，并加快转化研发流程设计。通过整合单细胞生物学、免疫学和内分泌肿瘤学，本综述揭示诊断盲区、指出药物再利用机会，并制定迈向个体化免疫治疗的路线图，以改善不同类型甲状腺癌患者的结局。
Thyroid cancer (TC) is now among the fastest-growing solid tumours, yet therapeutic gains remain limited for poorly differentiated, anaplastic and medullary variants whose median survivals are measured in months. Once guided chiefly by histology and single-gene assays, immunotherapy is being reshaped by single-cell profiling, which exposes the cellular mosaics that arbitrate response and resistance. Dissection of more than 150-000 tumour- and immune-cell transcriptomes has uncovered follicular-like, partial EMT-like and dedifferentiated thyrocyte states embedded within 'hot' (CD8 hi IFN- hi ), 'cold' (CD8 lo ) and 'excluded' (stroma-walled) immune niches; these phenotypes correlate with PD-1/LAG-3 expression, macrophage polarisation and radio-iodine refractoriness. Functional studies reveal that SPP1-CD44 and GAS6-AXL crosstalk licenses epithelial-mesenchymal transition while VSIG4 + macrophages blunt cytotoxic T-cell activity, collectively undermining checkpoint blockade. Spatial transcriptomics corroborates these insights, mapping PD-L1-high tumour islets millimetres from CXCL13-rich tertiary lymphoid structures, whereas CITE-seq quantifies actionable checkpoints and cytokine receptors across patient biopsies. Emerging therapeutics mirror this granular knowledge: combinatorial PD-1 + LAG-3 inhibition, CSF-1R-directed macrophage re-programming and TSH-receptor-targeted CAR-T cells are advancing through early-phase trials, while ex-vivo single-cell pharmacotyping aligns drug cocktails with an individual's tumour ecosystem. Early lenvatinib-pembrolizumab or selpercatinib-nivolumab trials show ~40% ORR but grade-3 hypertension >60%, prompting staggered-start designs. These advances sharpen pathogenetic resolution, refine patient selection and accelerate translational pipeline design. By integrating single-cell biology, immunology and endocrine oncology, this review identifies diagnostic blind spots, spotlights drug-repurposing opportunities and charts a roadmap toward personalised immunotherapeutic strategies capable of improving outcomes across the diverse spectrum of thyroid cancer.
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