胰腺导管腺癌 (PDAC) 是一种侵袭性癌症，没有有效的治疗方法，预后不良，导致美国所有癌症相关死亡人数的 7%。考虑到这种侵袭性癌症缺乏有效的治疗方法，迫切需要确定更新、更有效的治疗策略。聚肌苷-聚胞苷酸 (pIC) 是一种合成的双链 RNA (dsRNA)，可直接激活树突状细胞和自然杀伤细胞，抑制肿瘤生长。当使用聚乙烯亚胺 (PEI)、pIC-PEI 将 pIC 递送到细胞质中时，PDAC 中会诱导程序性细胞死亡。将 [pIC]PEI 转染到 PDAC 细胞中可抑制生长，促进毒性自噬，并在动物模型的体外和体内诱导细胞凋亡。KPC 转基因小鼠模型重现了患者 PDAC 的发育，用于探究完整免疫系统的作用体内 PDAC 对 [pIC]PEI 的反应。监测终点为抗肿瘤功效和生存率。对肿瘤微环境（TME）和脾脏中的免疫细胞、细胞因子和趋化因子以及巨噬细胞极化进行综合分析。胞质递送[pIC]PEI可诱导免疫活性小鼠体内细胞凋亡并激发强烈的抗肿瘤免疫。 [pIC]PEI 免疫刺激特性的机制涉及 Stat1 激活，导致 CCL2 和 MMP13 刺激，从而引发巨噬细胞极化。 [pIC]PEI 通过 AKT-XIAP 通路诱导细胞凋亡，并通过 PDAC 中的 IFNγ-Stat1-CCL2 信号通路诱导巨噬细胞分化和 T 细胞激活。在转基因肿瘤小鼠模型中，[pIC]PEI 促进强大而深远的抗肿瘤活性，这意味着刺激免疫系统有助于生物活性。当与标准护理 (SOC) 治疗（即吉西他滨）联合使用时，[pIC]PEI 的抗 PDAC 效果会增强。 总之，[pIC]PEI 治疗对正常胰腺细胞无毒性，同时显示出强细胞毒性PDAC 具有强大的免疫激活活性，使其在单独使用或与 SOC 治疗剂联合使用时成为一种有吸引力的治疗方法，有可能提供安全有效的治疗方案，并具有 PDAC 有效治疗的转化潜力。© 作者（或其作者）雇主）2023。CC BY-NC 允许重复使用。不得商业再利用。请参阅权利和权限。由英国医学杂志出版。

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective therapies and with poor prognosis, causing 7% of all cancer-related fatalities in the USA. Considering the lack of effective therapies for this aggressive cancer, there is an urgent need to define newer and more effective therapeutic strategies. Polyinosine-polycytidylic acid (pIC) is a synthetic double-stranded RNA (dsRNA) which directly activates dendritic cells and natural killer cells inhibiting tumor growth. When pIC is delivered into the cytoplasm using polyethyleneimine (PEI), pIC-PEI, programmed-cell death is induced in PDAC. Transfection of [pIC]PEI into PDAC cells inhibits growth, promotes toxic autophagy and also induces apoptosis in vitro and in vivo in animal models.The KPC transgenic mouse model that recapitulates PDAC development in patients was used to interrogate the role of an intact immune system in vivo in PDAC in response to [pIC]PEI. Antitumor efficacy and survival were monitored endpoints. Comprehensive analysis of the tumor microenvironment (TME) and immune cells, cytokines and chemokines in the spleen, and macrophage polarization were analyzed.Cytosolic delivery of [pIC]PEI induces apoptosis and provokes strong antitumor immunity in vivo in immune competent mice with PDAC. The mechanism underlying the immune stimulatory properties of [pIC]PEI involves Stat1 activation resulting in CCL2 and MMP13 stimulation thereby provoking macrophage polarization. [pIC]PEI induces apoptosis via the AKT-XIAP pathway, as well as macrophage differentiation and T-cell activation via the IFNγ-Stat1-CCL2 signaling pathways in PDAC. In transgenic tumor mouse models, [pIC]PEI promotes robust and profound antitumor activity implying that stimulating the immune system contributes to biological activity. The [pIC]PEI anti-PDAC effects are enhanced when used in combination with a standard of care (SOC) treatment, that is, gemcitabine.In summary, [pIC]PEI treatment is non-toxic toward normal pancreatic cells while displaying strong cytotoxic and potent immune activating activities in PDAC, making it an attractive therapeutic when used alone or in conjunction with SOC therapeutic agents, potentially providing a safe and effective treatment protocol with translational potential for the effective therapy of PDAC.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.