Eradication of CSCs: the roadmap for curing cancer.

Cancer treatment failure mostly involves the insensitivity of a small, heterogeneous fraction of cancer cells within the tumor mass, endowed with extraordinary plasticity and the ability to self-renew and metastasize [1, 2]. These cells, termed cancer stem cells (CSCs) are, in general, resistant to conventional anti-cancer treatments [1, 2]. Radioand chemotherapy can even result in the enrichment of this cell subset [1, 2]. A cancer research ambition of the last decades is to develop therapies that target the dynamic nature of CSCs and hamper the potential of non-CSCs to switch to CSC-like cells. Several strategies to target CSC-supporting pathways, that are currently under investigation in clinical trials, include impairment of mitochondria, either biogenesis and the metabolism, particularly the oxidative phosphorylation system; contrasting angiogenesis; redirect the CSC genetic program with epigenetic modulators [3]. A caveat is, however, emerging because of the intraand intertumoral diversity of CSCs and the not negligible toxicity of the molecular inhibitors that undermine the success of CSC-targeted approaches [3]. CSCs have a special immunoediting capacity, a process that leads the immune system to play cooperative roles in tumorigenesis and metastasis. Recent findings show that genes active in the embryo, like Sox2, Oct4, Hippo/ YAP [4], and members of the stemness-associated Wntsignaling pathway [5] contribute to immune evasion of CSC through transcriptional activation of PDL1 expression while disarming dendritic cells. It is worth noting that CSC-enriched subpopulations often show prominent aspects of epithelial-to-mesenchymal transition (EMT) [2]. Inherent cellular plasticity and chronic inflammatory signals associated with mesenchymal differentiation of cancer cells contribute to immune escape through multiple routes, particularly, Research Perspective