Autophagy–Apoptosis Crosstalk in Cancer: Mechanisms, Signaling Pathways, and Therapeutic Targeting

Autophagy and apoptosis are two evolutionarily conserved catabolic processes that play important roles in maintaining cellular homeostasis and in determining cell fate when cells are exposed to various stresses in vivo. The interaction between autophagy and apoptosis has been studied extensively in cancer research, and it has been shown to affect cancer initiation and tumor formation, disease progression, therapeutic resistance, and overall survival. Autophagy typically functions as a cytoprotective mechanism in cancer cells subjected to metabolic, hypoxic, or therapeutic stress, whereas apoptosis primarily functions as an intrinsic programmed cell death pathway. While apoptosis and autophagy function as distinct pathways, there is significant molecular crosstalk, allowing cells to modulate their behavior from survival to death depending on the severity and duration of exposure to a given stressor and the cellular environment. This review examines the molecular landscape of the autophagy–apoptosis interplay in cancers, with special attention paid to the major signaling pathways involved and their biological outcomes in oncology. We examine the molecular mechanisms and signal transduction pathways involved in the crosstalk between autophagy and apoptosis in cancer. In particular, we focus on several key proteins that regulate this crosstalk, including kinases, caspases, heat shock proteins and transcription factors. Furthermore, we describe the major signal transduction pathways that regulate this crosstalk, including the PI3K/Akt/mTOR, MAPK, unfolded protein response, oxidative stress, and calcium signaling pathways. Additionally, we discussed how dysregulation of these pathways contributes to cancer progression and treatment resistance. Finally, we summarized the use of currently available therapeutic agents targeting the crosstalk between autophagy and apoptosis, including FDA-approved drugs and natural products, with the potential to enhance the effectiveness of anticancer treatments. A better understanding of this complex process will allow the development of new, precision-based, combination cancer therapies.