Pancreatic ductal adenocarcinoma carries a dismal prognosis, and outcomes have improved little with modern therapeutics. Checkpoint-based immunotherapy has failed to elicit responses in the vast majority of patients with pancreatic cancer. Alongside tumor cell–intrinsic mechanisms associated with oncogenic KRAS-induced inflammation, the tolerogenic myeloid cell infiltrate has emerged as a critical impediment to adaptive antitumor immune responses. Furthermore, the discovery of an intratumoral microbiome and the elucidation of host–microbe interactions that curtail antitumor immunity also present opportunities for intervention. Here we review the mechanisms of immunotherapy resistance in pancreatic ductal adenocarcinoma and discuss strategies to directly augment T cell responses in parallel with myeloid cell– and microbiome-targeted approaches that may enable immune-mediated control of this malignancy.

胰腺导管腺癌预后不良，现代治疗方法几乎没有改善预后。基于检查点的免疫疗法未能在绝大多数胰腺癌患者中引起反应。肿瘤细胞内在机制与致癌性KRAS相关诱导炎症，耐受性髓样细胞浸润已成为适应性抗肿瘤免疫反应的关键障碍。此外，肿瘤内微生物组的发现以及限制抗肿瘤免疫力的宿主-微生物相互作用的阐明也为干预提供了机会。在这里，我们回顾了胰腺导管腺癌免疫治疗耐药性的机制，并讨论了与髓样细胞和微生物组靶向方法并行直接增强T细胞反应的策略，这些方法可能使免疫介导地控制这种恶性肿瘤。