Serine is critical for supporting cancer metabolism, and depriving malignant cells of this nonessential amino acid exerts antineoplastic effects, in large part, through disrupting metabolic pathways. Given the intricate relationship between cancer metabolism and the immune system, the metabolic defects imposed by serine deprivation might impact tumor-targeting immunity. In this study, we demonstrated that restricting endogenous and exogenous sources of serine in colorectal cancer cells results in mitochondrial dysfunction, leading to mitochondrial DNA (mtDNA) accumulation in the cytosol and consequent cGAS-STING1-driven type I IFN secretion. Depleting mtDNA or blocking its release attenuated cGAS-STING1 activation during serine deprivation. In vivo studies revealed that serine deprivation limits tumor growth, accompanied by enhanced type I IFN signaling and intratumoral infiltration of immune effector cells. Notably, the tumor-suppressive and immune-enhancing effects of serine restriction were impaired by T-cell depletion and IFN receptor blockade. Moreover, disrupting cGAS-STING1 signaling in colorectal cancer cells limited the immunostimulatory and tumor-suppressive effects of serine deprivation. Lastly, serine depletion increased the sensitivity of tumors to an immune checkpoint inhibitor targeting PD-1. Taken together, these findings reveal a role for serine as a suppressor of antitumor immunity, suggesting that serine deprivation may be employed to enhance tumor immunogenicity and improve responsiveness to immune checkpoint inhibitors. Significance: Depriving cancer cells of serine provokes mitochondrial perturbations that induce cytosolic mitochondrial DNA accumulation and subsequent activation of cGAS-STING signaling, stimulating tumor-targeting immune responses that can be enhanced with PD-1 targeted therapy. See related commentary by Borges and Garg, p. 2569.

中文翻译：

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丝氨酸耗竭通过激活线粒体 DNA 介导的 cGAS-STING 信号传导来促进抗肿瘤免疫。


丝氨酸对于支持癌症代谢至关重要，剥夺恶性细胞的这种非必需氨基酸可以在很大程度上通过破坏代谢途径发挥抗肿瘤作用。鉴于癌症代谢与免疫系统之间的复杂关系，丝氨酸剥夺造成的代谢缺陷可能会影响肿瘤靶向免疫。在这项研究中，我们证明限制结直肠癌细胞中丝氨酸的内源和外源来源会导致线粒体功能障碍，导致线粒体DNA（mtDNA）在细胞质中积累，并随后cGAS-STING1驱动的I型IFN分泌。耗尽 mtDNA 或阻断其释放会减弱丝氨酸剥夺期间 cGAS-STING1 的激活。体内研究表明，丝氨酸剥夺限制了肿瘤生长，同时增强了 I 型 IFN 信号传导和免疫效应细胞的瘤内浸润。值得注意的是，丝氨酸限制的肿瘤抑制和免疫增强作用因 T 细胞耗竭和 IFN 受体阻断而受损。此外，破坏结直肠癌细胞中的cGAS-STING1信号传导限制了丝氨酸剥夺的免疫刺激和肿瘤抑制作用。最后，丝氨酸消耗增加了肿瘤对针对 PD-1 的免疫检查点抑制剂的敏感性。总而言之，这些发现揭示了丝氨酸作为抗肿瘤免疫抑制剂的作用，表明丝氨酸剥夺可用于增强肿瘤免疫原性并改善对免疫检查点抑制剂的反应性。 意义：剥夺癌细胞的丝氨酸会引发线粒体扰动，从而诱导胞质线粒体 DNA 积累并随后激活 cGAS-STING 信号传导，从而刺激肿瘤靶向免疫反应，而 PD-1 靶向治疗可以增强这种免疫反应。参见 Borges 和 Garg 的相关评论，第 17 页。 2569.