CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Beyond PD-1/PD-L1: Reprogramming the Gynecologic Tumor Microenvironment by Targeting TIGIT and Myeloid Suppression.
Beyond PD-1/PD-L1: Reprogramming the Gynecologic Tumor Microenvironment by Targeting TIGIT and Myeloid Suppression.
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靶向PD-1/PD-L1轴的免疫检查点抑制剂已改变肿瘤治疗格局，但其在妇科恶性肿瘤尤其是高级别浆液性卵巢癌中的疗效仍令人失望地有限。这种治疗耐药源于一个高度协调、多维度的免疫抑制性肿瘤微环境（TME），其特征为调节性T细胞（Tregs）、髓源性抑制细胞（MDSCs）以及抑制性细胞因子网络（IL-10、TGF-β、VEGF）的协同作用。新出现的证据将TIGIT定位为一个主检查点整合因子，协调调控CD8+ T细胞耗竭、NK细胞功能障碍和Treg介导的免疫抑制。PD-1和TIGIT的双重阻断是一种机制上合理的策略，用以瓦解这一免疫抑制堡垒。本综述综合了当前对妇科TME结构的认识，阐明了TIGIT/PD-1协同作用的分子和细胞基础，批判性评估了正在进行的临床转化工作，并提出一个整合框架，利用空间转录组学、单细胞分辨率免疫谱分析和患者来源实验模型来加速生物标志物驱动的治疗开发。
Immune checkpoint inhibitors targeting the PD-1 (Programmed Cell Death Protein 1)/PD-L1 (Programmed Death-Ligand 1) axis have transformed cancer therapeutics, yet their efficacy in gynecologic malignancies particularly high-grade serous ovarian carcinoma remains disappointingly limited. This therapeutic resistance stems from a highly orchestrated, multidimensional immunosuppressive tumor microenvironment (TME) characterized by the convergent actions of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and an inhibitory cytokine network (IL-10, TGF-β, VEGF).
Emerging evidence positions TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domain) as a master checkpoint integrator that coordinately regulates CD8+ T-cell exhaustion, NK-cell dysfunction, and Treg-mediated suppression. Dual blockade of PD-1 and TIGIT represents a mechanistically rational strategy to dismantle this immunosuppressive fortress.
This review synthesizes current understanding of the gynecologic TME architecture, delineates the molecular and cellular basis for TIGIT/PD-1 synergy, critically evaluates ongoing clinical translation efforts, and proposes an integrative framework leveraging spatial transcriptomics, single-cell resolution immunoprofiling, and patient-derived experimental models to accelerate biomarker-driven therapeutic development.
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