Intravenous pharmacologic ascorbate as a redox modulator and chemosensitizer in targeted Cancer therapies

Intravenous pharmacologic ascorbate represents a re-emerging oncologic adjunct that exploits concentration-dependent pro-oxidant effects to selectively induce oxidative stress in malignant cells while preserving normal tissue. Supported by recent clinical data in metastatic pancreatic ductal adenocarcinoma, where high-dose ascorbate combined with gemcitabine and nab-paclitaxel has improved survival outcomes, this review proposes a broader therapeutic paradigm. This paper presents a hypothesis-driven translational perspective that synthesises current mechanistic evidence with a novel therapeutic proposal. Using Brentuximab Vedotin-based therapy for CD30-positive lymphomas as a representative model, we delineate the multi-mechanistic potential of intravenous pharmacologic ascorbate to enhance targeted treatment regimens. Intravenous pharmacologic ascorbate may act as both a redox disruptor and chemosensitizer-amplifying antibody-drug conjugate cytotoxicity through oxidative stress potentiation, apoptotic enhancement, and tumour microenvironment modulation. While preclinical evidence from related chemotherapy contexts suggests potential for synergistic interactions, direct evidence for this specific combination is currently lacking, and the mechanisms discussed remain hypothetical until validated in appropriate models. Notably, the redox-modulating properties of intravenous pharmacologic ascorbate could theoretically address common resistance pathways in cancer, such as the upregulation of endogenous antioxidant defences. Furthermore, emerging data suggests intravenous pharmacologic ascorbate may also influence epigenetic regulation in cancer cells through modulation of α-ketoglutarate-dependent dioxygenases, including ten-eleven translocation enzymes and histone demethylases, potentially reversing hypermethylation-associated silencing of tumour suppressor genes. This paper advocates for preclinical validation followed by well-designed phase II clinical trials to evaluate the safety, efficacy, and pharmacodynamics of intravenous pharmacologic ascorbate combined with targeted therapies. If the hypothesised benefits are confirmed, this approach could position intravenous pharmacologic ascorbate as an accessible, low-toxicity adjunct capable of improving long-term outcomes and quality of life for patients with aggressive malignancies.