Abstract 6607: Serine depletion promotes antitumor immunity throughmitochondrial DNA-mediated cGAS/STING1 activation

Abstract Serine is critical for supporting cancer metabolism, and as such, depriving malignant cells of this non-essential amino acid exerts anticancer effects, in large part, through disrupting their metabolic pathways. However, the impact of these metabolic defects on tumor-targeting immunity remains poorly understood. Here, we show that restricting endogenous and exogenous serine in colorectal cancer (CRC) cells results in mitochondrial dysfunction coupled to cytosolic mitochondrial DNA accumulation and cGAS/STING1-dependent type I interferon secretion. Serine-deprived tumors have suppressed growth, accompanied by type I interferon signaling and tumor infiltration by immune effector cells. Blocking cGAS/STING1 signaling in tumor cells limits the immunostimulatory and anticancer effects of serine deprivation. Moreover, serine-depleted tumors exhibit increased sensitivity to a programmed cell death 1 blocker. Lastly, transcriptomic data from human CRCs suggest that malignant lesions with reduced serine abundance have higher immune infiltration. Taken together, our findings reveal a novel role for serine as a gatekeeper of mitochondrial integrity and hence a suppressor of anticancerimmunity. Citation Format: Suchandrima Saha, Monisankar Ghosh, Li Jinyu, Asher Wen, Lorenzo Galluzzi, Luis Martinez, David C. Montrose. Serine depletion promotes antitumor immunity throughmitochondrial DNA-mediated cGAS/STING1 activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6607.