低剂量间歇性化疗（LDM chemotherapy）是一种应用常规化疗药物低剂量进行频繁而连续的化疗方式，正逐渐成为一种有前景的化疗利用形式。LDM 化疗对免疫调节具有效应，然而其潜在机制尚未完全明确。在本研究中，我们发现通过 LDM 化疗抑制肿瘤生长依赖于 CD8+T 细胞的激活。LDM 化疗可通过刺激癌细胞特异性 I 型干扰素（IFN）的诱导作用，增强 CD8+T 细胞的细胞毒作用。在机制上，LDM 化疗引发线粒体功能障碍和活性氧（ROS）的产生。ROS 引发细胞质线粒体 DNA（mtDNA）的氧化反应，被 cGAS-STING 所感知，进而在癌细胞中诱导 I 型 IFN 的产生。此外，cGAS-STING-IFN 轴增加了 PD-L1 表达并预测了对化疗免疫联合治疗的有利临床反应。抗氧化剂 N-乙酰半胱氨酸（N-acetylcysteine）抑制了氧化 mtDNA 引起的 I 型 IFN 的产生，并减弱了 LDM 化疗与 PD-L1 阻断联合治疗的疗效。本研究揭示了靶向肿瘤内氧化 mtDNA 感知在 LDM 化疗介导的 CD8+T 细胞免疫应答激活中的关键作用。这些发现可能为设计癌症患者的联合免疫治疗提供新的见解。Copyright © 2023. Published by Elsevier B.V.

Low-dose metronomic (LDM) chemotherapy, the frequent and continuous use of low doses of conventional chemotherapeutics, is emerging as a promising form of chemotherapy utilization. LDM chemotherapy exerts immunomodulatory effects. However, the underlying mechanism is not fully understood. Here we found that suppressing tumor growth by LDM chemotherapy was dependent on the activation of CD8+T cells. LDM chemotherapy potentiated the cytotoxic function of CD8+T cells by stimulating cancer-cell autonomous type I interferon (IFN) induction. Mechanistically, LDM chemotherapy evoked mitochondrial dysfunction and increased reactive oxygen species (ROS) production. ROS triggered the oxidation of cytosolic mtDNA, which was sensed by cGAS-STING, consequently inducing type I IFN production in the cancer cells. Moreover, the cGAS-STING-IFN axis increased PD-L1 expression and predicted favorable clinical responses to chemoimmunotherapy. Antioxidant N-acetylcysteine inhibited oxidized mtDNA-induced type I IFN production and attenuated the efficacy of combination therapy with LDM chemotherapy and PD-L1 blockade. This study elucidates the critical role of intratumoral oxidized mtDNA sensing in LDM chemotherapy-mediated activation of CD8+T cell immune response. These findings may provide new insights for designing combinatorial immunotherapy for cancer patients.Copyright © 2023. Published by Elsevier B.V.