Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment

SIMPLE SUMMARY: The tumor microenvironment (TME) is a complicated network, and several promising TME-targeted therapies, such as immunotherapy and targeted therapies, are now facing problems over low response rates and drug resistance. Vitamin C (VitC) has been extensively studied as a dietary nutrient and multi-targeted natural drug for fighting against tumor cells. The focus has been recently on its crucial functions in the TME. Here, we discuss the potential mechanisms of VitC in several specialized microenvironments, characterize the current status of its preclinical and clinical applications, and offer suggestions for future studies. This article is intended to provide basic researchers and clinicians with a detailed picture of VitC targeting the tumor microenvironment. ABSTRACT: Based on the enhanced knowledge on the tumor microenvironment (TME), a more comprehensive treatment landscape for targeting the TME has emerged. This microenvironment provides multiple therapeutic targets due to its diverse characteristics, leading to numerous TME-targeted strategies. With multifaced activities targeting tumors and the TME, vitamin C is renown as a promising candidate for combination therapy. In this review, we present new advances in how vitamin C reshapes the TME in the immune, hypoxic, metabolic, acidic, neurological, mechanical, and microbial dimensions. These findings will open new possibilities for multiple therapeutic avenues in the fight against cancer. We also review the available preclinical and clinical evidence of vitamin C combined with established therapies, highlighting vitamin C as an adjuvant that can be exploited for novel therapeutics. Finally, we discuss unresolved questions and directions that merit further investigation.