Natural Immunomodulators Targeting Cancer Stem Cells: A Scoping Review of Mechanisms and Therapeutic Potential

Background:Cancer stem cells (CSCs) are a group of cells that are resistant to treatment and are protected by animmunosuppressive tumor microenvironment (TME). They are not well targeted by standardtherapies. Natural immunomodulators, due to their diverse bioactivity against both CSC stemness andTME immunosuppression, constitute a promising yet inadequately delineated therapeutic avenue.Methods:A systematic scoping review was performed in accordance with PRISMA 2020 guidelines, utilizingScopus and PubMed from January 2021 to March 2026. A Boolean search that combined terms forCSC, natural immunomodulators, TME, and signaling pathways found 126 records (112 from Scopusand 14 from PubMed). After removing 14 duplicates, 112 records were screened for their titles andabstracts. 54 of these records were then checked to see if they were eligible for full text. Using pre-setinclusion criteria—peer-reviewed studies on natural compounds with known immunomodulatory andCSC-targeting activity—resulted in 36 final inclusions. Data were organized into a structured matrixand then put together by theme.Results:We found thirty-six studies that fit into five groups: CSC targeting (n=31), TME remodeling (n=26),drug resistance reversal (n=12), nanoformulation (n=12), and direct immunomodulation (n=4).Resveratrol, EGCG, isoliquiritigenin, silibinin, morusin, quercetin, and shikonin exhibited synergisticeffects on the Wnt/β-catenin, STAT3, HIF-1α, and CD73/adenosine pathways. Flavonoid-mediatedCD73 inhibition in triple-negative breast cancer augmented tumor-infiltrating lymphocyte density by3.2-fold while concurrently suppressing ALDH⁺ CSC subpopulations. Shikonin and ipilimumabtogether showed that they could work together to stop CSCs and let T cells into the body. Thisconnects research on natural compounds to clinical immunotherapy.Final Thoughts:Natural immunomodulators have two effects: they fight CSC and change the TME through convergentsignaling pathways. This makes them good partners for checkpoint immunotherapy. It is necessary toconduct clinical evaluations of these agents as TME-priming strategies in tumor environmentsenriched with cancer stem cells (CSCs).