A comprehensive review published in Genes & Diseases by authors from Capital Medical University and the National Clinical Research Center for Digestive Diseases synthesizes current mechanistic, preclinical, and clinical evidence, reframing pharmacologic ascorbate as a multi-targeted therapeutic strategy rather than an alternative remedy.

The review highlights a fundamental distinction between oral and intravenous vitamin C administration. While oral supplementation is tightly regulated and produces only micromolar plasma concentrations, intravenous delivery achieves millimolar levels capable of exerting tumor-selective cytotoxic effects. At pharmacological concentrations, vitamin C functions as a pro-oxidant, generating hydrogen peroxide within the tumor microenvironment. Cancer cells, characterized by elevated iron pools and compromised redox buffering systems, are particularly susceptible to iron-dependent oxidative stress, resulting in DNA damage, metabolic disruption, and cell death.

Beyond oxidative stress, HDVC influences cancer biology through epigenetic remodeling, signal transduction regulation, and immune modulation. By enhancing the activity of TET dioxygenases, vitamin C restores DNA demethylation patterns and reactivates tumor suppressor genes. It also suppresses oncogenic signaling pathways such as HIF-1 and NF-κB, attenuating angiogenesis, inflammation, and tumor progression. Importantly, emerging evidence demonstrates that HDVC enhances anti-tumor immunity by promoting T-cell infiltration, augmenting dendritic cell function, and synergizing with immune checkpoint inhibitors—suggesting a role in converting immunologically “cold” tumors into more responsive phenotypes.

Preclinical studies across multiple tumor types consistently demonstrate selective cytotoxicity and therapeutic synergy when HDVC is combined with chemotherapy, radiotherapy, targeted therapy, or immunotherapy. Clinically, early-phase trials indicate that intravenous HDVC is safe and well tolerated, frequently reducing treatment-related toxicity and improving quality of life.
However, variability in dosing strategies, administration sequences, tumor specificity, and patient selection has contributed to inconsistent efficacy outcomes in larger trials.

The review also discusses emerging strategies such as nano-formulated vitamin C, designed to improve tumor targeting, enhance intracellular delivery, and overcome rapid renal clearance. Despite encouraging data, significant challenges remain, including the need for standardized dosing protocols, biomarker-driven patient stratification, and large-scale randomized trials. The authors call for rigorous translational studies to define optimal integration of HDVC into precision oncology frameworks.
Collectively, this review reframes HDVC not as an alternative therapy, but as a biologically rational, multi-targeted adjunct that exploits tumor metabolic vulnerabilities and immune plasticity.

Future research priorities include rigorous phase III trials, biomarker-driven patient stratification, and optimized dosing regimens to establish HDVC’s definitive role in precision oncology.

Reference

Title of Original Paper: High-dose vitamin C: A promising anti-tumor agent, insight from mechanisms, clinical research, and challenges

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101742

Funding Information:

• The National Key Technologies R&D Program of China (No. 2017YFC0110904)
• Noncommunicable Chronic Diseases-National Science and Technology Major Project (China) (No. 2024ZD0520302)
• Beijing Hospitals Authority Clinical Medicine Development (China) (No. ZLRK202302)
• National Natural Science Foundation of China (No. 82101923)
• Beijing Municipal Administration of Hospitals' Youth Programme (China) (No. QML20230106)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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