Abstract：
Immune checkpoint blockade (ICB) has significantly improved the prognosis of patients with cancer, although the majority of such patients achieve low response rates; consequently, new therapeutic approaches are urgently needed. The upregulation of sialic acid-containing glycans is a common characteristic of cancer-related glycosylation, which drives disease progression and immune escape via numerous pathways. Herein, the development of self-assembled core-shell nanoscale coordination polymer nanoparticles loaded with a sialyltransferase inhibitor, referred to as NCP-STI which effectively stripped diverse sialoglycans from cancer cells, providing an antibody-independent pattern to disrupt the emerging Siglec-sialic acid glyco-immune checkpoint is reported. Furthermore, NCP-STI inhibits sialylation of the concentrated nucleoside transporter 1 (CNT1), promotes the intracellular accumulation of anticancer agent gemcitabine (Gem), and enhances Gem-induced immunogenic cell death (ICD). As a result, the combination of NCP-STI and Gem (NCP-STI/Gem) evokes a robust antitumor immune response and exhibits superior efficacy in restraining the growth of multiple murine tumors and pulmonary metastasis. Collectively, the findings demonstrate a novel form of small molecule-based chemo-immunotherapy approach which features sialic acids blockade that enables cooperative effects of cancer cell chemosensitivity and antitumor immune responses for cancer treatment.
摘要：
免疫检查点阻断（ICB）显著改善了癌症患者的预后，尽管大多数此类患者的反应率较低；因此，迫切需要新的治疗方法。含唾液酸的聚糖的上调是癌症相关糖基化的共同特征，通过多种途径驱动疾病进展和免疫逃逸。在这里，开发自组装的核壳纳米配位聚合物纳米粒子负载唾液酸转移酶抑制剂，被称为NCP-STI，它有效地从癌细胞中剥离了不同的唾液酸聚糖，报道了提供抗体非依赖性模式来破坏新出现的Siglec-唾液酸糖免疫检查点。此外，NCP-STI抑制浓缩核苷转运蛋白1（CNT1）的唾液酸化，促进抗癌剂吉西他滨（Gem）的细胞内积累，并增强宝石诱导的免疫原性细胞死亡（ICD）。因此,NCP-STI和Gem（NCP-STI/Gem）的组合激发了强大的抗肿瘤免疫反应，并在抑制多种小鼠肿瘤的生长和肺转移方面表现出优异的功效。总的来说，这些研究结果证明了一种新形式的基于小分子的化学免疫治疗方法,该方法的特点是唾液酸阻断,使癌细胞化学敏感性和抗肿瘤免疫应答在癌症治疗中发挥协同作用.
