The Role of PI3K/AKT Signalling Pathway in Cancer Stem Cells: Emerging Therapeutic Targets and Resistance Mechanisms

Cancer stem cells (CSCs) are an insignificant, however enormous population of tumor cells that display capacities of self-renewal, differentiation, and tumor initiation, consequently being the core feature in cancer progression, recurrence, and drug resistance. The phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) is one of the most critical signalling cascades regulating CSCs and controlling their stemness, survival, evasion of the immune system under stressful conditions, as well as metabolic reprogramming. This review provides an overview of the morphological features and functional aspects of the PI3K/AKT immune cascade and pathway, and how it essentially connects with both upstream and downstream effectors in CSC biology. The cross-communication of PI3K/AKT with other pathways, e.g., Wnt, Notch, and Hedgehog, is elaborated to emphasize the redundancy of the networks facilitating CSC maintenance and drug resistance. Additionally, we provide an in-depth scrutiny of the processes through which PI3K/AKT signalling leads to CSC resistance to chemotherapy, radiotherapy, and targeted therapy, as well as their plasticity, metastasis, and immune escape mechanisms. Current and future therapeutic approaches targeting the PI3K/AKT axis, such as small molecule inhibitors, combination therapy, and drug delivery nanotechnology, are also discussed. Finally, we present clinical issues and prospects for improving CSC-based therapy by using PI3K/AKT blockade to eliminate resistance and induce protracted, long-lasting cancer remission.