Vitcylation of Lysine: The Novel Mechanism of Vitamin C in Tumor Treatment

Abstract

Vitamin C (vitC), an essential nutrient for human health, has critical roles in numerous biological processes. VitC’s potential in disease prevention and treatment is a focus of ongoing research. Recent clinical studies have highlighted its promising effects in combating various tumor diseases, thus spurring further exploration of its anti-tumor mechanisms. Historically, the known anti-tumor mechanisms of vitC have included redox regulation and epigenetic modifications. He et al. have now uncovered a novel pathway in which covalent modification directly targets immune signaling proteins (Cell, 2025, 188, 1858–1877. DOI: 10.1016/j.cell.2025.01.043). These findings, particularly lysine vitcylation, substantially change the understanding of vitC’s mechanistic landscape. This Commentary comprehensively analyzes He’s study elucidating the key mechanisms underlying vitC’s anti-tumor efficacy. Furthermore, it thoroughly examines the newly proposed mechanism and discusses potential implications for clinical applications as well as future challenges.

Keywords

Cancer therapy / Immune activation / Lysine vitcylation / Vitamin C

References

[1] He X, Wang Q, Cheng X, Wang W, Li Y, et al. Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response. Cell 2025; 188(7): 1858-77 [PMID: 40023152 DOI: 10.1016/j.cell.2025.01.043]

[2] Wang Y, Dong L, Zhao M, Yin S, Da P, et al. Causal relationship between circulating vitamin C and 25-hydroxyvitamin D concentrations and common mental disorders - a Mendelian randomization study. Food Sci Human Well 2024; 13(4): 1877-85. [DOI: 10.26599/FSHW.2022.9250156]

[3] Hamdi E, Hidouri S, Muniz-Gonzalez A-B, Kechnebbou M, Amara S. Harnessing silica nanoparticles grafted with ascorbic acid to alleviate oxidative stress and impaired brain activity in rats. Nano TransMed 2025; 4: 100074. [DOI: 10.1016/j.ntm.2025.100074]

[4] Wang J, Liao ZX. Research progress of microrobots in tumor drug delivery. Food Med Homol 2024; 1(2): 9420025. [DOI: 10.26599/FMH.2024.9420025]

[5] Li MY, Gu A, Li J, Tang N, Matin M, et al. Exploring food and medicine homology: potential implications for cancer treatment innovations. Acta Materia Medica 2025; 4(2): 200-6. [DOI: 10.15212/amm-2025-0003]

[6] Agathocleous M, Meacham CE, Burgess RJ, Piskounova E, Zhao Z, et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 2017; 549(7673): 476-81. [DOI: 10.1038/nature23876]

[7] Cimmino L, Dolgalev I, Wang Y, Yoshimi A, Martin GH, et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell 2017; 170(6): 1079-95. [PMID: 28823558 DOI: 10.1016/j.cell.2017.07.032]

[8] Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 2015; 350(6266): 1391-6. [PMID: 26541605 DOI: 10.1126/science.aaa5004]

[9] Ngo B, Van Riper JM, Cantley LC, Yun J. Targeting cancer vulnerabilities with high-dose vitamin C. Nat Rev Cancer 2019; 19(5): 271-82. [PMID: 30967651 DOI: 10.1038/s41568-019-0135-7]

[10] Magrì A, Germano G, Lorenzato A, Lamba S, Chilà R, et al. High-dose vitamin C enhances cancer immunotherapy. Sci Transl Med 2020; 12(532): eaay8707. [PMID: 32102933 DOI: 10.1126/scitranslmed.aay8707]

[11] Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci 2005; 102: 13604-609. [PMID: 16157892 DOI: 10.1073/pnas.0506390102]

[12] Alyatkin S, Sigurdsson H, Askitopoulos A, Töpfer JD, Lagoudakis PG. Quantum fluids of light in all-optical scatterer lattices. Nat Commun 2021; 12(1): 5571. [PMID: 34552069 DOI: 10.1038/s41467-021-25845-4]

[13] Huang M, Gong G, Deng Y, Long X, Long W, et al. Crosstalk between cancer cells and the nervous system. Med Adv 2023; 1(3): 173-89. [DOI: 10.1002/med4.27]

[14] Stark GR, Darnell JE Jr. The JAK-STAT pathway at twenty. Immunity 2012; 36(4): 503-14. [PMID: 22520844 DOI: 10.1016/j.immuni.2012.03.013]

[15] Weinert BT, Schölz C, Wagner SA, Iesmantavicius V, Su D, et al. Lysine succinylation is a frequently occurring modification in prokaryotes and eukaryotes and extensively overlaps with acetylation. Cell Rep 2013; 4(4): 842-51. [PMID: 23954790 DOI: 10.1016/j.celrep.2013.07.024]

[16] López-Otín C, Galluzzi L, Freije JMP, Madeo F, Kroemer G. Metabolic control of longevity. Cell 2016; 166(4): 802-21. [PMID: 27518560 DOI: 10.1016/j.cell.2016.07.031]

[17] Xue JH, Chen GD, Hao F, Chen H, Fang Z, et al. A vitamin-C-derived DNA modification catalysed by an algal TET homologue. Nature 2019; 569(7757): 581-5. [DOI: 10.1038/s41586-019-1160-0]

[18] Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015; 27(4): 450-61. [PMID: 25858804 DOI: 10.1016/j.ccell.2015.03.001]

[19] Monti DA, Mitchell E, Bazzan AJ, Littman S, Zabrecky G, et al. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS One 2012; 7(1): e29794. [PMID: 22272248 DOI: 10.1371/journal.pone.0029794]