Plant-Derived Compounds as Potential Sensitizers to Immunotherapy in Melanoma

Compounds of plant origin have increasingly emerged as anticancer agents through direct cytotoxicity and sensitizing mechanisms. Melanoma remains the most aggressive form of skin cancer that exhibits a steadily increasing number of new cases globally each year, thus urgently requiring more effective therapeutic strategies. Therefore, phytochemicals can be considered promising candidates, particularly when used in combination with immune checkpoint inhibitors. Their ability to optimize therapeutic efficacy and strengthen antitumor immune responses is mediated through various mechanisms that include the stimulation of T cell activity, the regulation of the TME, the activation of intrinsic immune responses and cytokine signaling, and the regulation of immune checkpoints such as PD-1/PD-L1, CTLA-4, and LAG-3. Additionally, these compounds can alter key signaling pathways that control immune regulation. Nevertheless, the extrapolation of preclinical studies to clinical applications remains limited by insufficient clinical evidence, the lack of standardized therapeutic protocols, and poor pharmacokinetic behavior. Consequently, further studies are required in order to clarify their actual efficacy and to better define their role in modern oncology. This article aims to review the mechanisms that underlie the anticancer sensitizing activity of major classes of plant-derived compounds such as polyphenols, flavonoids, terpenoids, alkaloids, and isothiocyanates. The available preclinical and clinical evidence were reported together with their potential synergistic effects when combined with immune checkpoint inhibitors. An important aspect related to the anticancer effects of these compounds lies in their ability to simultaneously target multiple signaling pathways. Furthermore, advanced formulations such as nanoparticulated delivery systems are discussed as strategies to optimize their clinical application and therapeutic outcomes.