Table 2.
The Potential Therapeutic Strategies for CSCs.
| Therapeutic Strategies | Target | Mechanism | Treatment | References |
|---|---|---|---|---|
| Targeted therapies | CD133 | suppressed tumor growth, induced apoptosis | anti-CD133-drug conjugate (AC133-vcMMAF) | [183] |
| EpCAM | decreased cell number, tumorigenicity, spheroid formation and invasiveness | siRNA | [184,185] | |
| CD44 | suppressed aggressiveness, migration and adhesion | siRNA | [186] | |
| CD44v | inhibited cell growth and activated cell death | cystine–glutamate transporter (xCT) inhibitor sulfasalazine | [56] | |
| CD24 | reduced invasiveness | siRNA | [52] | |
| CD147 | decreased cell migration and invasion | siCD147 | [68] | |
| CXCR4 | suppressed the motility of the CD24+ cells | AMD3100 (CXCR4 inhibitor) | [53] | |
| mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) | inhibited the motility of the CD24+ cells | U0126 (MEK/ERK inhibitor) | [53] | |
| IL-6/STAT3 signaling pathway | reduced mammosphere formation | let-7c/miR-99a/miR-125b | [188] | |
| Immune therapies | cytotoxic T lymphocyte associated protein 4 (CTLA-4) | evaded immune surveillance: regulation of T-cell tolerance | anti-CTLA-4 monoclonal antibodies, ipilimumab | [144,189] |
| programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) | evaded immune surveillance | anti-PD-1 antibody pembrolizumab; anti-PD-L1 inhibitor nivolumab |
[144,189,190] | |
| CTLA-4 and PD-1 | evaded immune surveillance | nivolumab and Ipilimumab (Phase II) | [191] | |
| CTLA-4 and PD-L1 | evaded immune surveillance | durvalumab (PD-L1 inhibition) and tremelimumab (CTLA4 inhibition) (Phase I/II) |
[191] | |
| Combined therapies | chemokine receptor CXCR4 and hypoxia-inducible miR-210 | inhibited cell migration; showed cytotoxic activity towards CCA cells and reduced the number of cancer stem-like cells; reversed hypoxia-induced drug resistance | combination PCX/anti-miR-210 nanoparticle | [192] |
| Gemcitabine (GEM) and Metronidazole (MNZ) | suppressing ALDH activity, leading to decreased invasiveness and enhanced chemosensitivity | MNZ-induced mesenchymal–epithelial transition (MET) and enhancing chemosensitivity via increasing equilibrative nucleoside transporter 1 (ENT1) and reducing ribonucleotide reductase M1 (RRM1) | [193] | |
| Pembrolizumab + Capecitabine/Oxaliplatin | evaded immune surveillance; inhibited cell growth |
immunotherapy + chemotherapy (Phase II) | [191] | |
| Nivolumab + Gemcitabine/Cisplatin or Ipilimumab |
evaded immune surveillance; inhibited cell growth |
immunotherapy + chemotherapy (Phase II) | [191] | |
| Durvalumab + Tremelimumab + TACE/RFA or Cryoablation |
evaded immune surveillance; destruction of tumor |
immunotherapy + radiofrequency ablation (Phase I/II) |
[191] |