Targeting cancer stem cells with ribosome-inactivating proteins: from molecular mechanisms to clinical translation.

INTRODUCTION: Cancer stem cells (CSCs) are a rare but highly tumorigenic subpopulation that drives tumor initiation, therapeutic resistance, metastasis, and disease recurrence. Their intrinsic resistance to conventional therapies has prompted the development of targeted strategies capable of selectively eliminating CSCs while sparing normal cells and tissues. AREAS COVERED: This review summarizes the current understanding of ribosome-inactivating proteins (RIPs) as targeted therapeutics against CSCs. We discuss the structural and mechanistic features of RIPs, their ability to induce apoptosis and disrupt CSC-associated signaling pathways, and recent advances in RIP-based delivery platforms, including immunotoxins, ligand-directed conjugates, recombinant fusion proteins, and nanocarriers. Relevant literature was identified through comprehensive searches of PubMed, Scopus, and Web of Science, focusing on studies investigating RIPs in cancer biology, targeted therapy, and CSC-directed treatment. EXPERT OPINION: RIPs represent a promising class of biologics for CSC targeted therapy owing to their potent cytotoxic activity and versatility in targeted delivery systems. However, challenges including immunogenicity, systemic toxicity, intracellular delivery, and limited clinical translation remain significant barriers. Future advances in protein engineering and precision delivery technologies are expected to improve the therapeutic index of RIP based agents and accelerate their translation into clinically effective anticancer therapies.