Disulfiram bolsters T‐cell anti‐tumor immunity through direct activation of LCK‐mediated TCR signaling.

Activation of the T‐cell antigen receptor (TCR)–CD3 complex is critical to induce the anti‐tumor response of CD8+ T cells. Here, we found that disulfiram (DSF), an FDA‐approved drug previously used to treat alcohol dependency, directly activates TCR signaling. Mechanistically, DSF covalently binds to Cys20/Cys23 residues of lymphocyte‐specific protein tyrosine kinase (LCK) and enhances its tyrosine 394 phosphorylation, thereby promoting LCK kinase activity and boosting effector T cell function, interleukin‐2 production, metabolic reprogramming, and proliferation. Furthermore, our in vivo data revealed that DSF promotes anti‐tumor immunity against both melanoma and colon cancer in mice by activating CD8+ T cells, and this effect was enhanced by anti‐PD‐1 co‐treatment. We conclude that DSF directly activates LCK‐mediated TCR signaling to induce strong anti‐tumor immunity, providing novel molecular insights into the therapeutic effect of DSF on cancer. Synopsis: Enhancing activation of TCR‐CD3 complex in CD8+ T cell is a promising approach to achieve therapeutic antitumor immunity. Here, the FDA‐approved drug disulfiram (DSF) is found to bolster T‐cell responses in vitro and in vivo through a LCK‐mediated mechanism, providing valuable insights on drug repurposing in cancer immunotherapy. DSF directly activates the TCR signaling pathway.DSF binds to LCK via its N‐terminal Cys20/Cys23 residues, enhancing LCK kinase activity.DSF induces the production of IL‐2 and effector cytokines, promotes cell proliferation and metabolic reprogramming in CD8+ T cells.DSF shows potent anti‐tumor efficacy via the activation of CD8+ T cells. [ABSTRACT FROM AUTHOR]