Vitamin B6 preserves the stemness-like phenotypes and antitumor ability of CD8⁺ T cells

Tumor-infiltrating lymphocytes are usually dysfunctional but demonstrate stem cell-like behavior through unclear mechanisms. Here, we report that administration of vitamin B6 or its active form, pyridoxal phosphate (PLP), endows mouse and human CD8⁺ T cells with improved persistence, stemness-like phenotypes, and tumor clearance capabilities. Lowering PLP by pyridoxal kinase (PDXK) heterozygosity results in reduced T cell stemness-like properties and increased exhaustion phenotypes in tumors. Mechanistically, PLP preserves T cell function by directly binding to and inhibiting p70S6 kinase (p70S6K). Through limiting p70S6K-mediated BTB domain and CNC homolog 2 (BACH2) phosphorylation, PLP increases nuclear retention and functional activation of BACH2, promoting stemness gene expression while dampening exhaustion gene expression. In preclinical tumor models, PLP treatment improves the efficacy of anti-programmed death receptor 1 (PD-1) antibody therapy. Thus, our study reveals a pathway that preserves T cell functional stemness-like phenotypes to drive the acquisition of antitumor immunity, highlighting the clinical potential of vitamin B6/PLP-enhanced T cell function strategies in cancer immunotherapy.