S-ketamine dampens effector T-cell function, thereby promoting tumor progression.

BACKGROUND: S-ketamine, a widely used clinical analgesic drug and also employed as a therapeutic regimen in cancer pain management, but whether S-ketamine influence on effector immune cells when conquering tumor cells remains unclear. METHODS: In this study, we established effector T cells (chimeric antigen receptor T cells (CAR- T cells) and TCR-engineered T cells (TCR-T cells)) and treated with different concentrations of S-ketamine and investigated its impact on antitumor efficacy of effective T cell in vitro and in vivo assays. RESULTS: Our findings demonstrated that S-ketamine treatment induced apoptosis in CAR- T and TCR-T cells, with higher concentrations leading to significant cell death. Furthermore, during coculture with target cells, increasing S-ketamine concentrations progressively dampened the early and late activation, impaired the tumor-killing capacity of both CAR-T and TCR-T cells, accompanied by reduced secretion of effector cytokines- particularly a striking downregulation of TNF-α production. Meanwhile, the expression of immune checkpoint receptors in T cells was upregulation under target cell stimulation and S- ketamine treatment. Consistent with in vitro findings, escalating S- ketamine concentrations dampened the tumor inhibition of TCR-T cells in a xenograft tumor model, and also diminished the tumor-infiltrating capability of TCR-T cells. CONCLUSIONS: our study reveals that S- ketamine suppresses the cytotoxic function and promotes exhaustive phenotype of effector T cells when conquering the target cells, and providing some new guides in clinical use of S-ketamine on cancer pain therapy.