Abstract
Immune checkpoint inhibitor (ICI) therapy has revolutionized metastatic melanoma treatment, yet only a subset of patients respond effectively, and the treatment can induce a variety of immune-related adverse events (irAEs), including colitis. The gut microbiome plays a critical role in determining patient responses to immunotherapy, prompting exploration of gut-modifying strategies such as prebiotics, probiotics, and fecal microbiota transplantation (FMT) to overcome both primary and acquired resistance and improve treatment outcomes. Prebiotics, defined as dietary substrates that selectively support the growth and/or activity of beneficial gut microorganisms, represent a feasible and safe strategy for microbiome reshaping. Plant-derived prebiotics like castalagin, inulin, fructooligosaccharides, galactooligosaccharides, mushroom extract, kale extract, and konjac glucomannan offer unique advantages over synthetic or animal-derived alternatives due to their natural fiber content alongside their ability to enhance gut microbial diversity. Prebiotics are known to achieve health benefits by selectively stimulating beneficial gut bacteria, producing short-chain fatty acids (SCFAs) that modulate the host immune system, suppressing pathogenic microbes, enhancing mucin production, and modulating systemic and gut-associated immune responses. SCFAs generated through prebiotic fermentation influence host innate and adaptive immunity and regulate metabolic activity via inhibition of histone deacetylases (HDACs), influencing mTOR/MAPK signaling and cytokine production. They also act as ligands for G-protein-coupled receptors (GPCRs), altering intracellular calcium and cAMP to modulate immune cell gene expression. However, the specific mechanisms by which individual prebiotics interact with host genetics, beneficial gut bacteria, and their metabolites are not very well understood. This is crucial to optimize their therapeutic potential in cancer immunotherapy. This review synthesizes current evidence on plant-derived prebiotics, highlighting the impact of beneficial gut bacteria and their metabolites. Given their established safety for human consumption, prebiotics represent a promising, low-risk option to improve gut microbiome composition and potentially enhance immunotherapy and clinical outcomes in cancer.