改善胰腺导管腺癌（PDAC）患者的预后需要探索新的治疗靶点。迄今为止，大多数 PDAC 疗法的研究，包括抑制小泛素样修饰（SUMO 化）的研究，都集中在 PDAC 上皮细胞生物学上，但 SUMO 化发生在多种细胞类型中。 SUMO化在肿瘤微环境中影响 PDAC 的机制尚不清楚。我们使用临床相关的原位 PDAC 小鼠模型来研究使用特定的临床阶段化合物 TAK-981 抑制 SUMO 化的效果。与体外抑制 PDAC 细胞增殖相反，TAK-981 在体内赋予的生存益处依赖于 T 细胞的存在，这表明适应性抗肿瘤免疫的诱导是体内 SUMO 化抑制的重要抗肿瘤作用。为了了解这种适应性抗肿瘤免疫是如何促进的，我们通过以单细胞分辨率进行转录组分析，研究了体内 SUMO 化抑制如何改变主要细胞类型/亚型及其在 PDAC 肿瘤微环境中的通讯，这使得我们可以在原位小鼠中绘制细胞图谱基于基因表达谱的人类 PDAC 肿瘤细胞模型。研究结果通过流式细胞术、免疫荧光、IHC、蛋白质印迹和 qPCR 得到进一步验证。这里提供的单细胞转录组数据集提出了几种增强适应性免疫反应的组合策略，这对于 PDAC 患者的持久疾病控制是必要的。©2024 美国癌症研究协会。

Improvement of outcome in patients with pancreatic ductal adenocarcinoma (PDAC) requires exploration of novel therapeutic targets. Thus far, most studies of PDAC therapies, including those inhibiting small ubiquitin-like modifications (SUMOylation), have focused on PDAC epithelial cell biology, yet SUMOylation occurs in a variety of cell types. The mechanisms by which SUMOylation impacts PDAC in the context of its tumor microenvironment are poorly understood. We used clinically relevant orthotopic PDAC mouse models to investigate the effect of SUMOylation inhibition using a specific, clinical-stage compound, TAK-981. In contrast to its inhibition of PDAC cell proliferation in vitro, the survival benefit conferred by TAK-981 in vivo is dependent on the presence of T cells, suggesting that induction of adaptive antitumor immunity is an important antitumor effect of SUMOylation inhibition in vivo. To understand how this adaptive antitumor immunity is promoted, we investigated how SUMOylation inhibition in vivo alters major cell types/subtypes and their communications in the PDAC tumor microenvironment by performing transcriptomic analyses at single-cell resolution, which allowed mapping of cells in our orthotopic mouse model to cells in human PDAC tumors based on gene expression profiles. Findings are further validated by flow cytometry, immunofluorescence, IHC, western blots, and qPCR. The single-cell transcriptome dataset provided here suggests several combination strategies to augment adaptive immune responses that are necessary for durable disease control in patients with PDAC.©2024 American Association for Cancer Research.