Cancer remains the second leading cause of death worldwide . Despite significant efforts from researchers and clinicians, cancer is still considered a death sentence, which is even true for high-grade malignancies. High mortality among cancer patients largely occurs because of tumors’ resistance to existing therapies, which leads to recurrence. To develop effective therapies, it is important to understand the process of tumorigenesis and the specific molecular pathways that need to be targeted to overcome therapeutic resistance.
Based on extensive research, it has been identified that the majority of tumors are derived from cancer stem cells (CSCs), which are transformed from normal stem cells (SCs) or differentiated cells due to various genetic or epigenetic alterations . In the late 1990s, John Edgar Dick’s group pioneered the discovery of cancer stem cells (CSCs) by proposing a leukemia-initiating cell hierarchy model. This model suggested that human acute myeloid leukemia (AML) follows a hierarchical organization originating from primitive hematopoietic cells .
Subsequently, similar populations of CSCs were identified in various solid tumors, spanning breast, brain, prostate, ovarian, gastric, lung, and pancreatic cancers These CSCs were identified as a rare population of primitive cells that were long lived, could exist in proliferative or quiescent/dormant stages, were apoptosis resistant, multipotent, and most importantly possessed self-renewal capacity. This led to the proposal that CSCs are the seed of cancer and are responsible for tumor initiation, progression, and cellular heterogeneity, resistance to therapies, recurrence, and metastasis. However, the molecular mechanisms determining the proliferation/differentiation, chemoresistance, and other characteristics of CSCs are highly complex and remain poorly defined .
Autophagy is a catabolic process that involves the degradation of dysfunctional or unwanted cellular components through cellular lysosomal machinery. Autophagy serves to maintain cellular homeostasis under physiological conditions and is also activated under various pathological conditions and determines the outcome of the disease. The role of autophagy in CSC maintenance, proliferation, differentiation, and resistance to therapies is emerging . Thus, autophagy is considered a potential therapeutic target in various cancers to eliminate CSCs. The present review explores recent advances in understanding the role of autophagy in CSCs with a special focus on various molecular mechanisms involved, which can act as potential therapeutic targets in otherwise therapy-resistant CSCs. The present review covers the basic mechanisms of CSC biology and sheds light on the relationship between autophagy and CSCs via the regulation of cellular dormancy, metabolic pathways, mitochondrial regulation, and therapeutic response. Understanding autophagy-related biological targets will contribute to the design of innovative therapeutic strategies aimed at the selective elimination of CSCs or induction of their differentiation.