胰腺癌 (PC) 的免疫抑制环境是治疗的一个重大障碍，导致生存统计数据在 5 年来几乎没有变化。在这里，我们提出了一种联合治疗方法，包括立体定向体放射治疗 (SBRT) 和直接递送至小鼠胰腺肿瘤的 IL-12 mRNA 脂质纳米颗粒。这种治疗方法对原发性和转移性模型均有效，在两种情况下均实现了治愈。 IL-12 蛋白浓度是短暂的并且主要集中于肿瘤。耗尽 CD4 和 CD8 T 细胞会消除治疗效果，证实它们对于治疗反应至关重要。对 SBRT/IL-12 mRNA 治疗的肿瘤进行的单细胞 RNA 测序表明，不仅 T 细胞耗竭完全丧失，而且还存在大量高度增殖和效应 T 细胞亚型。 SBRT 引发 T 细胞受体克隆扩增，而 IL-12 则赋予这些细胞效应功能。这是第一份证明 SBRT 和 IL-12 mRNA 在 PC 中的效用的报告。这项研究证明了由放射疗法和免疫疗法组成的新型联合疗法在小鼠胰腺肿瘤中的应用。这种疗法可以有效治疗局部和转移性疾病，这表明它可能有潜力治疗五年来生存率没有显着提高的癌症。

The immunosuppressive milieu in pancreatic cancer (PC) is a significant hurdle to treatments, resulting in survival statistics that have barely changed in 5 decades. Here we present a combination treatment consisting of stereotactic body radiation therapy (SBRT) and IL-12 mRNA lipid nanoparticles delivered directly to pancreatic murine tumors. This treatment was effective against primary and metastatic models, achieving cures in both settings. IL-12 protein concentrations were transient and localized primarily to the tumor. Depleting CD4 and CD8 T cells abrogated treatment efficacy, confirming they were essential to treatment response. Single cell RNA sequencing from SBRT/IL-12 mRNA treated tumors demonstrated not only a complete loss of T cell exhaustion, but also an abundance of highly proliferative and effector T cell subtypes. SBRT elicited T cell receptor clonal expansion, whereas IL-12 licensed these cells with effector function. This is the first report demonstrating the utility of SBRT and IL-12 mRNA in PC.This study demonstrates the use of a novel combination treatment consisting of radiation and immunotherapy in murine pancreatic tumors. This treatment could effectively treat local and metastatic disease, suggesting it may have the potential to treat a cancer that has not seen a meaningful increase in survival in 5 decades.