Autophagy occurs at a basal level in all cells and can be induced by various signals and cellular stresses. Macroautophagy (referred to hereafter as autophagy) is a highly conserved catabolic process with the formation of double membrane vesicles called autophagosomes that engulf cellular proteins and organelles for delivery to the lysosome (Fig. In this review, we focus on how we may be able to leverage our understanding of these interactions and mechanisms to better harness the power of autophagy manipulation in cancer care. Additionally, we now have a better mechanistic understanding of how autophagy interacts with cell death pathways to alter therapeutic responses to cancer treatments. Autophagy can have both tumor cell autonomous and non-autonomous promoting effects on tumor growth and both the degradative process of autophagy itself related but distinct degradative processes as well as non-degradative activities of the autophagy machinery can affect tumor cell behavior. These studies focus on blocking the recycling mechanism of autophagy to prevent the renewal of cellular proteins and other molecules that help cancer cells survive under stressful conditions such as hypoxia, nutrient deprivation and to enhance other cancer treatments including chemotherapy and radiation. Conversely, in advanced cancers, while both enhancing autophagy and inhibiting it have been proposed as therapeutic strategies, clinical interventions to deliberately manipulate autophagy in cancer therapy are already underway with the vast majority focused on inhibiting autophagy. Thus, in premalignant lesions, enhancing autophagy might prevent cancer. Once malignant cancers are fully established, increased autophagy enables tumor cell survival and growth. For example, decreased autophagy is associated with infiltration of regulatory T cells that suppress the immune system and decrease effective immunosurveillance allowing for increased tumor initiation. Autophagy also works with immunosurveillance to provide a non-cellular autonomous cancer prevention method. This helps prevent chronic cellular damage and transition into a cancer-initiating cell. Autophagy maintains normal cell homeostasis through the removal of oncogenic protein substrates, toxic unfolded proteins and damaged organelles. It is felt that autophagy is an important mechanism to prevent cancer development in both cell autonomous and non-cell autonomous methods. Indeed, although it is well accepted that autophagy is important in many diseases, until now, the majority of clinical studies that involve deliberate attempts to manipulate autophagy are in cancer therapy, almost always in patients with advanced disease. Its role in cancer therapy is particularly important. During fusion with the lysosome (blue oval) LC3–PE associated with the outer membrane is cleaved and recycled by ATG4 while LC3–PE associated with the inner-membrane is degraded by lysosomal proteases along with the cargo of the autophagosome.In 2016, Yoshinori Ohsumi was awarded the Nobel Prize for Physiology or Medicine for his work on autophagy and its impact in the study of human health and disease. The membrane elongation is dependent on the ATG12–ATG5-ATG16L1 conjugation system. ( D) The autophagosomal membrane (orange crescent) is studded with LC3–PE (stylized in black). ( C) The two ubiquitin-like conjugation systems essential for membrane elongation are outlined schematically. BECN1 is inhibited when bound by anti-apoptotic BCL2, which results in downregulated autophagy. UVRAG and ATG14 are found in BECN1 complexes in a mutually exclusive manner. ( B) The PtdIns3K complex is assembled at the site of the nascent autophagosomal membrane. ( A) Dephosphorylated ULK1 dissociates from the MTOR complex and phosphorylates itself, ATG13 and RB1CC1 to induce the nucleation phase. Autophagy is a complex degradation process in which general cytoplasm or organelles are engulfed by a double-membrane bound structure and degraded and recycled following fusion with a lysosome.
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