Therapies that synergistically stimulate immunogenic cancer cell death (ICD), inflammation and immune priming are of great interest for cancer immunotherapy. However, even multi-agent therapies often fail to trigger all of the steps necessary for self-sustaining antitumor immunity. Here we describe self-replicating RNAs encapsulated in lipid nanoparticles (LNP), which combine three key elements: (1) an LNP composition that potently promotes ICD, (2) RNA that stimulates danger sensors in transfected cells and (3) RNA-encoded interleukin (IL)-12 for modulation of immune cells. Intratumoral administration of LNP-replicons led to high-level expression of IL-12, stimulation of a type I interferon response and cancer cell ICD, resulting in a highly inflamed tumor microenvironment and priming of systemic antitumor immunity. In several mouse models of cancer, a single intratumoral injection of LNP-replicons eradicated large established tumors, induced protective immune memory and enabled regression of distal uninjected tumors. LNP-replicons are thus a promising multifunctional single-agent immunotherapeutic.

协同刺激免疫原性癌细胞死亡 (ICD)、炎症和免疫启动的疗法对癌症免疫疗法非常感兴趣。然而，即使是多药剂疗法也常常无法触发自我维持抗肿瘤免疫所需的所有步骤。在这里，我们描述了封装在脂质纳米颗粒 (LNP) 中的自我复制 RNA，它结合了三个关键要素：(1) 有效促进 ICD 的 LNP 组合物，(2) 刺激转染细胞中危险传感器的 RNA 和 (3) RNA 编码白细胞介素 (IL)-12 用于调节免疫细胞。LNP复制子的瘤内给药导致IL-12的高水平表达，刺激I型干扰素反应和癌细胞ICD，导致高度发炎的肿瘤微环境和全身抗肿瘤免疫的启动。在几种癌症小鼠模型中，单次瘤内注射 LNP 复制子可根除已形成的大肿瘤，诱导保护性免疫记忆并使远端未注射肿瘤得以消退。因此，LNP 复制子是一种很有前途的多功能单药免疫治疗剂。