Oncolytic viruses (OVs), a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact, are emerging as promising living anticancer agents. Unlike traditional drugs composed of non-replicating compounds or biomolecules, the replicative nature of viruses confer unique pharmacokinetic properties that require further studies. Despite some pharmacokinetics studies of OVs, mechanistic insights into the connection between OV pharmacokinetics and antitumor efficacy remain vague. Here, we characterized the pharmacokinetic profile of oncolytic virus M1 (OVM) in immunocompetent mouse tumor models and identified the JAK‒STAT pathway as a key modulator of OVM pharmacokinetics. By suppressing the JAK‒STAT pathway, early OVM pharmacokinetics are ameliorated, leading to enhanced tumor-specific viral accumulation, increased AUC and , and improved antitumor efficacy. Rather than compromising antitumor immunity after JAK‒STAT inhibition, the improved pharmacokinetics of OVM promotes T cell recruitment and activation in the tumor microenvironment, providing an optimal opportunity for the therapeutic outcome of immune checkpoint blockade, such as anti-PD-L1. Taken together, this study advances our understanding of the pharmacokinetic-pharmacodynamic relationship in OV therapy.

中文翻译：

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通过抑制 JAK-STAT 通路增强溶瘤病毒 M1 的药代动力学

溶瘤病毒（OV）是一组具有复制能力的病毒，可以选择性地感染和杀死癌细胞，同时保持健康细胞完好无损，正在成为有前途的活抗癌剂。与由非复制化合物或生物分子组成的传统药物不同，病毒的复制性质赋予了独特的药代动力学特性，需要进一步研究。尽管对 OV 进行了一些药代动力学研究，但对 OV 药代动力学与抗肿瘤功效之间联系的机制了解仍然模糊。在这里，我们描述了溶瘤病毒 M1 (OVM) 在免疫活性小鼠肿瘤模型中的药代动力学特征，并确定 JAK-STAT 通路是 OVM 药代动力学的关键调节剂。通过抑制 JAK-STAT 通路，早期 OVM 药代动力学得到改善，从而增强肿瘤特异性病毒积累，增加 AUC 和 ，并提高抗肿瘤功效。 JAK-STAT 抑制后，OVM 改善的药代动力学并没有损害抗肿瘤免疫，而是促进了肿瘤微环境中 T 细胞的募集和激活，为免疫检查点阻断（例如抗 PD-L1）的治疗结果提供了最佳机会。总而言之，这项研究增进了我们对 OV 治疗中药代动力学-药效关系的理解。