Natural Compounds as Network-Level Modulators of Cancer Stem Cell Plasticity

Cancer stem cells (CSCs) drive therapeutic resistance and tumor relapse by exploiting redundant regulatory networks that integrate Wnt/β-catenin, Notch, and Hedgehog signaling with metabolic reprogramming, epigenetic plasticity, and tumor microenvironment crosstalk, a network architecture that renders single-pathway inhibition strategies insufficient. This review systematically examines evidence that natural compounds (curcumin, sulforaphane, resveratrol, EGCG, berberine, and quercetin) act as multitarget modulators of CSC plasticity, analyzing their molecular mechanisms of action in specific cancer models. Each compound engages distinct regulatory nodes: curcumin suppresses β-catenin nuclear translocation and STAT3 phosphorylation in lung cancer CSC models; sulforaphane represses ΔNp63α-driven stemness transcription in colorectal cancer and reduces CSC self-renewal in prostate and head and neck models; resveratrol dissociates the β-catenin–GLI-1 interaction in oral and lung CSC populations and induces Wnt/β-catenin-dependent autophagy in breast CSCs; EGCG inhibits DNMT and HDAC activity in glioblastoma and colorectal models; berberine activates AMPK-mediated suppression of mTORC1 in colorectal cancer; and quercetin suppresses PI3K/AKT/mTOR signaling while downregulating EMT transcription factors in breast and colorectal systems. We critically assess persistent methodological limitations, including bulk cell-line models, supraphysiological concentrations, and the absence of functional tumor-initiating validation, that currently prevent stronger translational conclusions. Natural compounds from Latin American biodiversity are identified as an underexplored source of CSC-active molecules. We conclude by defining the experimental standards required to reposition natural compounds as clinically relevant network-level modulators of CSC plasticity.