Natural compounds as immune checkpoint inhibitors in melanoma: a systematic review

Melanoma, the most lethal form of skin cancer, poses significant therapeutic challenges despite advances in immunotherapy. Natural compounds have emerged as promising adjuncts for modulating immune checkpoint pathways, including PD-1/PD-L1, CTLA-4, and LAG-3. A systematic review was conducted from inception to July 2025, searching the Web of Science, PubMed/MEDLINE, and Scopus. MeSH terms and keywords encompassed immune checkpoints, natural compounds (e.g., phytochemicals), and melanoma. We included original studies investigating natural compounds in melanoma models that reported outcomes related to immune checkpoint modulation. Nineteen preclinical studies met the inclusion criteria. Flavonoids (quercetin, apigenin, and luteolin) inhibited PD-L1 via JAK2/STAT3 and IFN-γ/STAT1 suppression. Emerging bioactive sources such as Polygonum minus and drimenol were identified as multi-target agents capable of reprogramming the tumor microenvironment. Alkaloids such as berberine promoted PD-L1 degradation through the CSN5-ubiquitin-proteasome axis. Nanocarrier-based delivery systems, particularly calcium carbonate nanoparticles, enhanced bioavailability and achieved synergistic efficacy with reduced systemic toxicity, highlighting a key strategy for clinical translation. Natural compounds offer a multi-targeted strategy to overcome melanoma resistance. While current preclinical evidence is promising, it remains hypothesis-generating. The findings suggest that phytochemicals can modulate multiple checkpoints with a favorable safety profile. Future research must focus on rigorous clinical trials to establish standardized dosing and validate safety margins for translating these agents into effective personalized melanoma immunotherapies.