Vitamin C Enhances Anticancer Immunity

Abstract

The molecular mechanisms underlying vitamin C’s anticancer activity remain unclear. Recently, multiple high-quality studies demonstrated several potentially novel functions of vitamin C in regulating anticancer immunity, including modulating T cell infiltration of tumor microenvironment as well as increasing cancer cell immunogenicity. (First online: June 4, 2023) REFERENCES Creagan ET, Moertel CG, O'Fallon JR, Schutt AJ, O'Connell MJ, Rubin J, et al. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer: a controlled trial. N Engl J Med 1979; 301(13):687–90. doi: https://dx.doi.org/10.1056/NEJM197909273011303 Moertel CG, Fleming TR, Creagan ET, Rubin J, O'Connell MJ, Ames MM. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy: a randomized double-blind comparison. N Engl J Med 1985; 312(3):137–41. doi: https://dx.doi.org/10.1056/NEJM198501173120301 Lin J, Cook NR, Albert C, Zaharris E, Gaziano JM, Van Denburgh M, et al. Vitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trial. J Natl Cancer Inst 2009; 101(1):14–23. doi: https://dx.doi.org/10.1093/jnci/djn438 Chen Q, Espey MG, Sun AY, Pooput C, Kirk KL, Krishna MC, et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci USA 2008; 105(32):11105–9. doi: https://dx.doi.org/10.1073/pnas.0804226105 Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K, et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 2015; 350(6266):1391–6. doi: https://dx.doi.org/10.1126/science.aaa5004 Magri A, Germano G, Lorenzato A, Lamba S, Chila R, Montone M, et al. High-dose vitamin C enhances cancer immunotherapy. Sci Transl Med 2020; 12(532). doi: 10.1126/scitranslmed.aay8707. Xu YP, Lv L, Liu Y, Smith MD, Li WC, Tan XM, et al. Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy. J Clin Invest 2019; 129(10):4316–31. doi: https://dx.doi.org/10.1172/JCI129317 Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet 2017; 18(9):517–34. doi: https://dx.doi.org/10.1038/nrg.2017.33 Luchtel RA, Bhagat T, Pradhan K, Jacobs WR, Jr., Levine M, Verma A, et al. High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model. Proc Natl Acad Sci USA 2020; 117(3):1666–77. doi: https://dx.doi.org/10.1073/pnas.1908158117 Morante-Palacios O, Godoy-Tena G, Calafell-Segura J, Ciudad L, Martinez-Caceres EM, Sardina JL, et al. Vitamin C enhances NF-kappaB-driven epigenomic reprogramming and boosts the immunogenic properties of dendritic cells. Nucleic Acids Res 2022; 50(19):10981–94. doi: https://dx.doi.org/10.1093/nar/gkac941