Cancer stem cells (CSCs) are considered as a small population of cells with stem-like properties within the tumor bulk, and are largely responsible for tumor recurrence, metastasis, and therapy resistance. CSCs share critical features with embryonic stem cells (ESCs). The pluripotent transcription factors (TFs) and developmental signaling pathways of ESCs are invariably hijacked by CSCs termed ‘oncofetal drivers’ in many cancers, which are rarely detectable in adult tissues. The unique expression pattern makes oncofetal proteins ideal therapeutic targets in cancer treatment. Therefore, elucidation of oncofetal drivers in cancers is critical for the development of effective CSCs-directed therapy. In this review, we summarize the common pluripotent TFs such as OCT4, SOX2, NANOG, KLF4, MYC, SALL4, and FOXM1, as well as the development signaling including Wnt/β-catenin, Hedgehog (Hh), Hippo, Notch, and TGF-β pathways of ESCs and CSCs. We also describe the newly identified oncofetal proteins that drive the self-renewal, plasticity, and therapy-resistance of CSCs. Finally, we explore how the clinical implementation of targeting oncofetal drivers, including small-molecule inhibitors, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) can facilitate the development of CSCs-directed therapy.

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