Disulfiram bolsters T‐cell anti‐tumor immunity through direct activation of LCK‐mediated TCR signaling
Open accessAbstract
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
DIS covalently binds to cysteine 20/cysteine 23 residues of 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.
“Mechanistically, DIS covalently binds to cysteine 20/cysteine 23 residues of 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.88”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [88]
DIS directly activates lymphocyte-specific protein tyrosine kinase-mediated T cell receptor signaling, which potently induces antitumor immunity independent of copper ion.
“Another novel insight into DIS’s anticancer effects involves its direct activation of lymphocyte-specific protein tyrosine kinase (LCK)-mediated T cell receptor (TCR) signaling, which potently induces antitumor immunity independent of copper ion.88”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [88]
The citation lists haven’t been fetched yet
References 39 · Cited by 45
Research works printed but not linked: 33
- Abraham RT, Weiss A (2004) Jurkat T cells and development of the T‐cell receptor signalling paradigm. Nat Rev Immunol 4: 301–308 · DOI
- Bommhardt U, Schraven B, Simeoni L (2019) Beyond TCR signaling: emerging functions of lck in cancer and immunotherapy. Int J Mol Sci 20: 3500 · DOI
- Brownlie RJ, Zamoyska R (2013) T cell receptor signalling networks: branched, diversified and bounded. Nat Rev Immunol 13: 257–269 · DOI · Paper page
- Buchtova T, Skrott Z, Chroma K, Rehulka J, Dzubak P, Hajduch M, Lukac D, Arampatzis S, Bartek J, Mistrik M (2021) Cannabidiol‐induced activation of the metallothionein pathway impedes anticancer effects of disulfiram and its metabolite CuET. Mol Oncol 16: 1541–1554 · DOI · Paper page
- Cao X (2016) Self‐regulation and cross‐regulation of pattern‐recognition receptor signalling in health and disease. Nat Rev Immunol 16: 35–50 · DOI
- Chan AC, Desai DM, Weiss A (1994) The role of protein tyrosine kinases and protein tyrosine phosphatases in T cell antigen receptor signal transduction. Annu Rev Immunol 12: 555–592 · DOI
- Chapman NM, Boothby MR, Chi H (2020) Metabolic coordination of T cell quiescence and activation. Nat Rev Immunol 20: 55–70 · DOI
- Davis SJ, van der Merwe PA (2011) Lck and the nature of the T cell receptor trigger. Trends Immunol 32: 1–5 · DOI
- Ehrlich LI, Ebert PJ, Krummel MF, Weiss A, Davis MM (2002) Dynamics of p56lck translocation to the T cell immunological synapse following agonist and antagonist stimulation. Immunity 17: 809–822 · DOI
- Gillis S, Watson J (1980) Biochemical and biological characterization of lymphocyte regulatory molecules. V. Identification of an interleukin 2‐producing human leukemia T cell line. J Exp Med 152: 1709–1719 · DOI
- Hu JJ, Liu X, Xia S, Zhang Z, Zhang Y, Zhao J, Ruan J, Luo X, Lou X, Bai Y et al (2020) FDA‐approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nat Immunol 21: 736–745 · DOI · Paper page
- Irvine DJ, Purbhoo MA, Krogsgaard M, Davis MM (2002) Direct observation of ligand recognition by T cells. Nature 419: 845–849 · DOI
- Jiao Y, Hannafon BN, Ding WQ (2016) Disulfiram's anticancer activity: evidence and mechanisms. Anticancer Agents Med Chem 16: 1378–1384 · DOI
- Joyce JA, Fearon DT (2015) T cell exclusion, immune privilege, and the tumor microenvironment. Science 348: 74–80 · DOI
- Kim PW, Sun ZY, Blacklow SC, Wagner G, Eck MJ (2003) A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8. Science 301: 1725–1728 · DOI
- Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy comes of age. Nature 480: 480–489 · DOI · Paper page
- Menk AV, Scharping NE, Moreci RS, Zeng X, Guy C, Salvatore S, Bae H, Xie J, Young HA, Wendell SG et al (2018) Early TCR signaling induces rapid aerobic glycolysis enabling distinct acute T cell effector functions. Cell Rep 22: 1509–1521 · DOI
- Nash T, Rice WG (1998) Efficacies of zinc‐finger‐active drugs against Giardia lamblia. Antimicrob Agents Chemother 42: 1488–1492 · DOI
- Nika K, Soldani C, Salek M, Paster W, Gray A, Etzensperger R, Fugger L, Polzella P, Cerundolo V, Dushek O et al (2010) Constitutively active Lck kinase in T cells drives antigen receptor signal transduction. Immunity 32: 766–777 · DOI
- Pai MY, Lomenick B, Hwang H, Schiestl R, McBride W, Loo JA, Huang J (2015) Drug affinity responsive target stability (DARTS) for small‐molecule target identification. Methods Mol Biol 1263: 287–298 · DOI
- Rice WG, Schaeffer CA, Harten B, Villinger F, South TL, Summers MF, Henderson LE, Bess JW, Arthur LO, McDougal JS et al (1993) Inhibition of HIV‐1 infectivity by zinc‐ejecting aromatic C‐nitroso compounds. Nature 361: 473–475 · DOI
- Roberts EW, Broz ML, Binnewies M, Headley MB, Nelson AE, Wolf DM, Kaisho T, Bogunovic D, Bhardwaj N, Krummel MF (2016) Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell 30: 324–336 · DOI
- Salmond RJ, Filby A, Qureshi I, Caserta S, Zamoyska R (2009) T‐cell receptor proximal signaling via the Src‐family kinases, Lck and Fyn, influences T‐cell activation, differentiation, and tolerance. Immunol Rev 228: 9–22 · DOI
- Shi X, Bi Y, Yang W, Guo X, Jiang Y, Wan C, Li L, Bai Y, Guo J, Wang Y et al (2013) Ca2+ regulates T‐cell receptor activation by modulating the charge property of lipids. Nature 493: 111–115 · DOI
- Smith‐Garvin JE, Koretzky GA, Jordan MS (2009) T cell activation. Annu Rev Immunol 27: 591–619 · DOI · Paper page
- Terashima Y, Toda E, Itakura M, Otsuji M, Yoshinaga S, Okumura K, Shand FHW, Komohara Y, Takeda M, Kokubo K et al (2020) Targeting FROUNT with disulfiram suppresses macrophage accumulation and its tumor‐promoting properties. Nat Commun 11: 609 · DOI
- Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, Rossen J, Joesch‐Cohen L, Humeidi R, Spangler RD et al (2022) Copper induces cell death by targeting lipoylated TCA cycle proteins. Science 375: 1254–1261 · DOI · Paper page
- Wang F, Beck‐Garcia K, Zorzin C, Schamel WW, Davis MM (2016) Inhibition of T cell receptor signaling by cholesterol sulfate, a naturally occurring derivative of membrane cholesterol. Nat Immunol 17: 844–850 · DOI
- Wang Q, Wang C, Li N, Liu X, Ren W, Wang Q, Cao X (2018) Condensin Smc4 promotes inflammatory innate immune response by epigenetically enhancing NEMO transcription. J Autoimmun 92: 67–76 · DOI
- Weiss A, Wiskocil RL, Stobo JD (1984) The role of T3 surface molecules in the activation of human T cells: a two‐stimulus requirement for IL 2 production reflects events occurring at a pre‐translational level. J Immunol 133: 123–128 · DOI
- Wu J, Li G, Li L, Li D, Dong Z, Jiang P (2021) Asparagine enhances LCK signalling to potentiate CD8(+) T‐cell activation and anti‐tumour responses. Nat Cell Biol 23: 75–86 · DOI
- Xu C, Gagnon E, Call ME, Schnell JR, Schwieters CD, Carman CV, Chou JJ, Wucherpfennig KW (2008) Regulation of T cell receptor activation by dynamic membrane binding of the CD3epsilon cytoplasmic tyrosine‐based motif. Cell 135: 702–713 · DOI
- Yang W, Bai Y, Xiong Y, Zhang J, Chen S, Zheng X, Meng X, Li L, Wang J, Xu C et al (2016) Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature 531: 651–655 · DOI · Paper page
- Authors
- Wang, Q., Zhu, T., Miao, N., Qu, Y., Wang, Z., Chao, Y., Wang, J., Wu, W., Xu, X., Xu, C., Xia, L., & Wang, F.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Wang, Qinlan
- Zhu, Ting
- Miao, Naijun
- Wang, Feng
- ORCID
- Venue
- The EMBO Journal
- Published
- 2022-05-31
- Volume
- 41
- Issue
- 16
- Pages
- e110636-e110636
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC9379552
- OpenAlex
- W4281656083
- Cited by
- 45
- References
- 39
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 14 · 2023: 2 · 2022: 2
- FWCI
- 3.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Key Research and Development Program of China (SQ2018YFA090045‐01)
- National Key Research and Development Program of ChinaNational Natural Science Foundation of China (82071852, 82003011)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- disulfiram, T cell receptor signaling, Lck kinase, CD8+ T cells, antitumor immunity, tyrosine kinase activation, covalent drug binding, interleukin-2, T cell metabolic reprogramming, melanoma, colon cancer, anti-PD-1 combination therapy
- MeSH terms
- Animals, Disulfiram, Lymphocyte Activation, Phosphorylation, Receptors, Antigen, T-Cell, Signal Transduction, CD8-Positive T-Lymphocytes, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
