Dual impacts of serine/glycine-free diet in enhancing antitumor immunity and promoting evasion via PD-L1 lactylation

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.