胰腺导管腺癌（PDAC）具有高度致死性且对免疫疗法具有抵抗力。尽管免疫调节剂（包括检查点抑制剂和疫苗）可以增强免疫识别，但很少有患者能获得临床疗效，因为肿瘤免疫微环境（TiME）主要由免疫抑制性骨髓细胞控制，从而抑制 T 细胞。据报道，磷酸二酯酶 5 (PDE5) 的抑制可下调免疫抑制性骨髓细胞中的代谢调节剂精氨酸酶和 iNOS，并增强对免疫敏感肿瘤（包括头颈癌）的免疫力。我们首次证明，将 PDE5 抑制剂他达拉非与间皮素特异性疫苗、抗 PD1 和抗 CTLA4 相结合，即使针对免疫抵抗性 PDAC，也能产生抗肿瘤功效。为了确定他达拉非赋予的免疫学优势，我们使用质谱流式细胞仪和 Domino 进行单细胞 RNA 分析来分析 TiME，以推断细胞间信号传导。我们的分析表明，他达拉非可对骨髓细胞进行重新编程，使其免疫抑制程度降低。此外，他达拉非与疫苗具有协同作用，增强 T 细胞活化，包括间皮素特异性 T 细胞。他达拉非治疗还与抗肿瘤反应重要的髓系 T 细胞信号轴（例如 Cxcr3、Il12）相关。我们的研究表明，PDE5 抑制与基于疫苗的免疫疗法相结合，可促进髓系细胞的促炎状态、T 细胞的激活并增强髓系-T 细胞的串扰，从而产生针对免疫抵抗性 PDAC 的抗肿瘤功效。

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and resistant to immunotherapy. Although immune recognition can be enhanced with immunomodulatory agents including checkpoint inhibitors and vaccines, few patients experience clinical efficacy because the tumor immune microenvironment (TiME) is dominated by immunosuppressive myeloid cells that impose T cell inhibition. Inhibition of phosphodiesterase-5 (PDE5) was reported to downregulate metabolic regulators arginase and iNOS in immunosuppressive myeloid cells and enhance immunity against immune-sensitive tumors including head and neck cancers. We show for the first time that combining a PDE5 inhibitor, tadalafil, with a mesothelin-specific vaccine, anti-PD1, and anti-CTLA4 yields antitumor efficacy even against immune-resistant PDAC. To determine immunologic advantages conferred by tadalafil, we profiled the TiME using mass cytometry and single-cell RNA analysis with Domino to infer intercellular signaling. Our analyses demonstrated that tadalafil reprograms myeloid cells to be less immunosuppressive. Moreover, tadalafil synergized with the vaccine, enhancing T cell activation including mesothelin-specific T cells. Tadalafil treatment was also associated with myeloid-T cell signaling axes important for antitumor responses (e.g., Cxcr3, Il12). Our study shows that PDE5 inhibition combined with vaccine-based immunotherapy promotes pro-inflammatory states of myeloid cells, activation of T cells, and enhanced myeloid-T cell crosstalk to yield antitumor efficacy against immune-resistant PDAC.