CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Targeting thymidylate synthase enhances CD8 + T-cell infiltration and inhibits tumor growth in cervical cancer.
Targeting thymidylate synthase enhances CD8 + T-cell infiltration and inhibits tumor growth in cervical cancer.
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宫颈癌（CESC）在临床上仍是一项重大挑战，主要原因在于对肿瘤微环境（TME）中免疫代谢交互作用的理解尚不完整，且缺乏可靠的免疫治疗分层生物标志物。胸苷酸合成酶（TYMS）是核苷酸合成中的关键酶，已被认为与肿瘤进展相关，但其作为CESC中免疫代谢调控因子的作用尚未被探索。通过整合47,589个细胞的单细胞RNA测序（scRNA-seq）、批量转录组学、功能实验和体内建模，我们阐明了TYMS的多方面功能。scRNA-seq分析揭示了在进展过程中从CD4+向耗竭CD8+T细胞优势的动态转变，这一过程由特定的配体-受体相互作用如PTPRC-MRC1所 orchestrate。
我们开发了一个稳健的T细胞相关预后特征，包含TYMS、MYO6、SPINT1和ESD，能够有效将患者分为不同的风险组，这些风险组在肿瘤干性、免疫浸润和免疫治疗反应方面存在差异。在机制上，TYMS沉默通过靶向miR-197-3p在体外促进肿瘤干性、迁移和侵袭。至关重要的是，在免疫健全小鼠模型中，TYMS敲低加速了肿瘤生长并强烈抑制了CD8+T细胞浸润，证明其在促进免疫逃逸中的作用。相反，TYMS过表达抑制了肿瘤发生。分子对接鉴定出脱氧尿苷单磷酸为TYMS的高亲和力抑制剂。
我们的研究结果表明，靶向胸苷酸合成酶可增强CD8+T细胞浸润并抑制宫颈癌中的肿瘤生长，确立TYMS为一个有前景的治疗靶点。
Cervical cancer (CESC) presents a significant clinical challenge, primarily due to an incomplete understanding of the immunometabolic crosstalk within the tumor microenvironment (TME) and the lack of reliable biomarkers for immunotherapy stratification. Thymidylate synthase (TYMS), a pivotal enzyme in nucleotide synthesis, has been implicated in tumor progression, but its role as an immunometabolic regulator in CESC remains unexplored.
Through an integrative approach combining single-cell RNA sequencing (scRNA-seq) of 47,589 cells, bulk transcriptomics, functional assays, and in vivo modeling, we delineated the multifaceted functions of TYMS. scRNA-seq analysis revealed a dynamic shift from CD4 + to exhausted CD8 + T-cell dominance during progression, orchestrated by specific ligand-receptor interactions like PTPRC-MRC1.
A robust T cell-associated prognostic signature comprising TYMS, MYO6, SPINT1 and ESD was developed, effectively stratifying patients into distinct risk groups with differential tumor stemness, immune infiltration, and response to immunotherapy.
Mechanistically, TYMS silencing promoted tumor stemness, migration, and invasion in vitro via targeting miR-197-3p. Crucially, in immunocompetent micemodel, TYMS knockdown accelerated tumor growth and potently suppressed CD8 + T-cell infiltration, demonstrating its role in promoting immune evasion. Conversely, TYMS overexpression suppressed tumorigenesis. Molecular docking identified Deoxyuridine Monophosphate as a high-affinity inhibitor of TYMS.
Our findings demonstrate that targeting thymidylate synthase enhances CD8 + T-cell infiltration and inhibits tumor growth in cervical cancer, establishing TYMS as a promising therapeutic target.
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