Dual impacts of serine/glycine-free diet in enhancing antitumor immunity and promoting evasion via PD-L1 lactylation
Huan Tong, Z. X. Jiang, Linlin Song, Keqin Tan, Xiaomeng Yin, Changtong He, Juan Huang, Xiaoyue Li, Xiaofan Jing, Yun Hong, Guangqi Li, Yunuo Zhao, Qianlong Kang, Yuhao Wei, Renwei Li, Zhiwen Long, Jun Yin, Qiang Luo, Xiao Liang, Yi Wan, Aiping Zheng, Nan Lin, Tao Zhang, Jiayi Xu, Xinggang Yang, Yuting Jiang, Yueyi Li, Xiang Yu, Yu Zhang, Lusi Feng, Zhen Lei, Hubing Shi, Xuelei Ma
Abstract
The effect of the serine/glycine-free diet (-SG diet) on colorectal cancer (CRC) remains unclear; meanwhile, programmed death-1 (PD-1) inhibitors are less effective for most CRC patients. Here, we demonstrate that the -SG diet inhibits CRC growth and promotes the accumulation of cytotoxic T cells to enhance antitumor immunity. Additionally, we also identified the lactylation of programmed death-ligand 1 (PD-L1) in tumor cells as a mechanism of immune evasion during cytotoxic T cell-mediated antitumor responses, and blocking the PD-1/PD-L1 signaling pathway is able to rejuvenate the function of CD8+ T cells recruited by the -SG diet, indicating the potential of combining the -SG diet with immunotherapy. We conducted a single-arm, phase I study (ChiCTR2300067929). The primary outcome suggests that the -SG diet is feasible and safe for regulating systemic immunity. Secondary outcomes include patient tolerability and potential antitumor effects. Collectively, our findings highlight the promising therapeutic potential of the -SG diet for treating solid tumors.