Autophagy in tumour immunity and therapy

Abstract

Autophagy is a regulated mechanism that removes unnecessary or dysfunctional cellular components and recycles metabolic substrates. In response to stress signals in the tumour microenvironment, the autophagy pathway is altered in tumour cells and immune cells -thereby differentially affecting tumour progression, immunity and therapy. In this Review, we summarize our current understanding of the immunologically associated roles and modes of action of the autophagy pathway in cancer progression and therapy, and discuss potential approaches targeting autophagy to enhance antitumour immunity and improve the efficacy of current cancer therapy.Autophagy is a tightly regulated and stress-induced catabolic pathway in all eukaryotes, during which double-membraned vesicles (called autophagosomes) are formed that engulf cellular targets -including damaged organelles, unfolded proteins and pathogens -and deliver them to the lysosome to be digested 1 . Selective forms of autophagy represent quality control and homeostatic mechanisms (BOX 1). The basic biology of autophagy has been extensively reviewed [2][3][4] . The canonical form of autophagy under discussion herein (more formally, macro-autophagy) is best understood under conditions of nutrient starvation 5 (FIG. 1). In the non-canonical autophagy pathway, proteins also function to lipidate microtubuleassociated protein 1A/1B-light chain 3 (LC3; also known as ATG8) family proteins on a single lipid bilayer. The most studied examples of this are LC3-associated phagocytosis (LAP) 6 and the more recently described LC3-associated endocytosis (LANDO) 7 (FIG. 1).

Calcium Signaling Regulates Autophagy and Apoptosis

“…Extracellular or intracellular pattern recognition receptors, including Toll-like receptors, together with advanced glycosylation end product-specific receptor, purinergic P2RX7 receptors and absent in melanoma 2, receive these signals and activate downstream signaling for calcium activation and the initiation of autophagy. Studies have shown that the E3 ligase TNF receptor-associated factor 6-mediated ubiquitination of Beclin 1 is critical for TLR4-triggered autophagy in macrophages, which releases Beclin 1 from its inhibitor BCL2 [108][109][110].…”

YAP activation attenuates toxicarioside G‑induced lethal autophagy arrest in SW480 colorectal cancer cells

“…Accumulating evidence has indicated that autophagy is involved in drug-mediated anticancer therapy ( 10 , 28 , 29 ); therefore, the present study investigated whether TCG induced autophagy in the SW480 cell line. First, LC3-II accumulation, a hallmark of autophagy, and the levels of Beclin 1 and Atg5, two autophagy-related proteins, were analyzed.…”

“…Autophagy is a conserved catabolic process whereby aggregated proteins or damaged organelles are sequestered by double-membrane autophagosomes and degraded in autolysosomes, which maintains cellular homeostasis under physiological conditions (9,10). Induction of autophagy has been observed in various types of cancer cells challenged with intra-and extracellular stresses; however, the role of autophagy in regulating the fate of cancer cells remains controversial (11)(12)(13).…”

Targeting Reactive Oxygen Species Capacity of Tumor Cells with Repurposed Drug as an Anticancer Therapy

“…In-depth evaluation of hydroxychloroquine, it revealed that it could be considered an effective autophagy inhibitor [ 144 ]. Autophagy is a self-degrading intracellular process involving tumor suppression and promotion [ 145 ]. However, inhibition of autophagy with hydroxychloroquine can not only hinder the autophagic protective effect but also increase dysfunctional mitochondria and ROS production, and a further study found that ROS was the main mechanism of enhanced cytotoxicity with autophagy inhibition [ 144 ].…”