Vitamin-mediated cancer immune reprogramming: Context-dependent mechanisms and translational perspectives

Abstract

Vitamins are increasingly recognized not as passive dietary cofactors or interchangeable antioxidants but as context-sensitive immunometabolic regulators that can reshape antigen presentation, natural killer (NK)-cell fitness, T-cell exhaustion, tumor-cell immunogenicity, and potential responsiveness to immune checkpoint inhibitor therapy. This review synthesizes mechanistic and translational evidence linking vitamins A, B, C, D, E, and K to anti-tumor immunity. We advance three organizing principles. First, vitamin biology is profoundly context-dependent: The same retinoid, calcitriol, ascorbate, or antioxidant pathway can enforce immune tolerance or restore cytotoxic immunity depending on dose, pharmacokinetics, tissue compartment, tumor genotype, cellular source, and treatment sequence. Second, vitamin actions extend beyond redox buffering to epigenetic and post-translational control, exemplified by vitamin C-driven TET-dependent remodeling and signal transducer and activator of transcription 1 lysine vitcylation, which amplifies interferon signaling and major histocompatibility complex-I antigen presentation in pre-clinical models. Third, vitamins hold promise as biomarker-guided adjuvants rather than empiric supplements; however, most candidate biomarkers, apart from serum 25-hydroxyvitamin D, tumor glucose transporter 1, aldehyde dehydrogenase, retinoic acid (RA) receptor activity, dendritic cell (DC) Src-homology-2-domain-containing protein-tyrosine phosphatase-1 (SHP1) protein tyrosine phosphatase signaling, or NK-cell metabolic fitness, lack prospective clinical validation in cancer patients. We integrate available clinical observations alongside pre-clinical mechanistic findings on vitamin D status monitoring during anti-programmed cell death 1 (PD-1) therapy, nicotinamide-expanded NK-cell adoptive transfer, retinoic-acid-pathway modulation for DC-based vaccines, pre-clinically described vitamin E-scavenger receptor class B member 1-SHP1 signaling, and pre-clinical pharmacological ascorbate combined with anti-PD-1 therapy. We therefore propose a precision vitamin-mediated immunotherapy framework that prioritizes deficiency correction, drug-like exposure, immune-contexture mapping, therapeutic sequencing, and mandatory prospective randomized validation. Notably, most biomarker-driven intervention strategies outlined in this review remain exploratory and are not ready for routine clinical application.

Keywords: Vitamins; Immunometabolism; Tumor microenvironment; Immune checkpoint inhibitor therapy; Dendritic cells; Natural killer cells; Precision vitamin immunotherapy

Core Tip: Vitamins are context-dependent immunometabolic regulators reshaping anti-tumor immunity and immune checkpoint inhibitor response beyond simple antioxidant function. This review summarizes mechanistic and translational evidence of vitamins A/B/C/D/E/K in tumor immunity, putting forward three core principles covering dose-dependent immune effects, epigenetic regulatory mechanisms, and biomarker-guided adjuvant application. We propose a precision vitamin-targeted immunotherapy framework combining deficiency correction, standardized supplementation and matched immune background to optimize tumor immunotherapy efficacy.