Abstract
Autophagy, a self-eating machinery, has been reported as an adaptive response to maintain metabolic homeostasis when cancer cells encounter stress. It has been appreciated that autophagy acts as a double-edge sword to decide the fate of cancer cells upon stress factors, molecular subtypes, and microenvironmental conditions. Currently, the majority of evidence support that autophagy in cancer cells is a vital mechanism bringing on resistance to current and prospective treatments, yet whether autophagy affects the anticancer immune response remains unclear and controversial. Accumulated studies have demonstrated that triggering autophagy is able to facilitate anticancer immunity due to an increase in immunogenicity, whereas other studies suggested that autophagy is likely to disarm anticancer immunity mediated by cytotoxic T cells and nature killer (NK) cells. Hence, this contradiction needs to be elucidated. In this review, we discuss the role of autophagy in cancer cells per se and in cancer microenvironment as well as its dual regulatory roles in immune surveillance through modulating presentation of tumor antigens, development of immune cells, and expression of immune checkpoints. We further focus on emerging roles of autophagy induced by current treatments and its impact on anticancer immune response, and illustrate the pros and cons of utilizing autophagy in cancer immunotherapy based on preclinical references.
Highlights
Autophagy, a self-eating machinery, has been reported as an adaptive response to maintain metabolic homeostasis when cancer cells encounter stress
Except for HIF-1α modulation in hypoxia-induced autophagy, hypoxia accompanied by glucose and amino acid deprivation results in HIF-independent autophagy triggered by AMPK activation and mammalian target of rapamycin (mTOR) inhibition [83]
Since hypoxia results in REDD1- or BCL2 Interacting Protein 3 (BNIP3)-mediated autophagy, as mentioned previously (Figure 1), studies have been carried out to examine whether there is a correlation between HIF-1α and BNIP3 or REDD1
Summary
An essential mechanism responsible for sustaining metabolism in eukaryotic cells, has been known over 50 years. The mechanism of autophagosome formation is well known, as described above, the key issue is why cells decide to undergo autophagy. ULK1–Atg13–FIP200 complex-mediated autophagosome formation or through TSC1/2 dependent or independent mTOR inhibition [6]. In addition to AMPK activation, hypoxia is capable of suppressing mTOR via BCL2 Interacting Protein 3 (BNIP3) and regulated in development and DNA damage responses 1 (REDD1), resulting in macroautophagy [7,8]. Atg-mediated autophagosome formation include growth factors such as insulin and their receptors, ER stress, and amino acid depletion. ER stress and amino acid depletion have been reported to increase the level of p62, which serves as adaptor of autophagy and interacts with LC3 for autophagosome formation [11]. Understanding the relationship between autophagy and these factors is needed for improvement of cancer immunotherapies or in combination with other treatments
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