肿瘤细胞治疗研究
英文原题：Activation of an adaptive antitumor immune response by the polymeric fluoropyrimidine CF10 involves TS/Top1 dual targeting.
Activation of an adaptive antitumor immune response by the polymeric fluoropyrimidine CF10 involves TS/Top1 dual targeting.
在体内，对携带原位MC38肝转移的C57BL/6小鼠进行CF10治疗，可增加CD4⁺、CD8⁺和γδ T细胞浸润，减少髓源性抑制细胞（MDSCs），并降低肝脏肿瘤负荷。
基于5-FU的方案仍是转移性结直肠癌（mCRC）治疗的基石，但持久缓解罕见。CF10是一种下一代聚合型氟嘧啶，在临床前模型中显示出优于5-FU的抗肿瘤活性。在此，我们评估了CF10是否能更有效地诱导免疫原性细胞死亡（ICD）并促进抗肿瘤免疫，同时表征其双重机制，涉及胸苷酸合成酶（TS）抑制以及通过Topoisomerase 1切割复合物（Top1cc）稳定化和γ-H2AX积累引起的复制应激。在小鼠（MC38）和人（HCT116）结直肠癌细胞中，CF10诱导的ICD标志物水平——细胞外ATP、HMGB1释放和表面钙网蛋白——显著高于5-FU，并引发强烈的Top1cc稳定化及γ-H2AX焦点形成。来自CF10处理细胞的条件培养基增强了树突状细胞（DC）成熟以及TNF-α、IL-1β、CCL2和CCL4的分泌。在体内，对携带原位MC38肝转移的C57BL/6小鼠进行CF10治疗，增加了CD4⁺、CD8⁺和γδ T细胞浸润，减少了髓源性抑制细胞（MDSCs），并降低了肝脏肿瘤负荷。CF10还减少了FoxP3⁺调节性T细胞和CD206⁺免疫抑制性巨噬细胞。与5-FU或未处理对照相比，使用CF10条件上清的DC疫苗适度延长了生存期并增加了肿瘤浸润T细胞。CF10引发双重作用机制——通过TS抑制和Top1cc依赖性复制应激（γ-H2AX）产生细胞毒性，并通过ICD诱导产生免疫原性——驱动强效DC激活和适应性免疫应答。这些发现使CF10成为mCRC一种有前景的免疫调节化疗药物，并支持临床评估，包括与免疫检查点阻断的联合策略。
5-Fluorouracil (5-FU)-based regimens remain the backbone of therapy for metastatic colorectal cancer (mCRC), yet durable responses are rare.CF10, a next-generation polymeric fluoropyrimidine, has demonstrated superior antitumor activity compared with 5-FU in preclinical models. Here, we evaluated whether CF10 more effectively induces immunogenic cell death (ICD) and promotes antitumor immunity, while characterizing its dual mechanism involving thymidylate synthase (TS) inhibition and replication stress through Topoisomerase 1 cleavage complex (Top1cc) stabilization and γ-H2AX accumulation. In murine (MC38) and human (HCT116) colorectal cancer cells, CF10 induced significantly higher levels of ICD markers-extracellular ATP, HMGB1 release, and surface calreticulin-than 5-FU and triggered robust Top1cc stabilization with γ-H2AX foci formation. Conditioned media from CF10-treated cells enhanced dendritic cell (DC) maturation and secretion of TNF-α, IL-1β, CCL2, and CCL4. In vivo, CF10 treatment in C57BL/6 mice bearing orthotopic MC38 liver metastases increased CD4⁺, CD8⁺, and γδ T-cell infiltration, reduced myeloid-derived suppressor cells (MDSCs), and decreased hepatic tumor burden. CF10 also decreased FoxP3⁺ regulatory T cells and CD206⁺ immunosuppressive macrophages. DC vaccination using CF10-conditioned supernatants modestly extended survival and increased tumor-infiltrating T cells compared with 5-FU or untreated controls. CF10 elicits a dual-action mechanism-cytotoxicity via TS inhibition and Top1cc-dependent replication stress (γ-H2AX) and immunogenicity through ICD induction-driving potent DC activation and adaptive immune responses. These findings position CF10 as a promising immunomodulatory chemotherapeutic for mCRC and support clinical evaluation, including combination strategies with immune checkpoint blockade.
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