Autophagy modulation: a prudent approach in cancer treatment?

Autophagy is a tightly controlled process comprising lysosomal degradation and recycling of cellular proteins and organelles. In cancer, its paradoxical dual role of cytoprotection and cytotoxicity is context-dependent and controversial. Autophagy primarily acts as a mechanism of tumour suppression, by maintenance of genomic integrity and prevention of proliferation and inflammation. This, combined with immune-surveillance capabilities and autophagy’s implicated role in cell death, acts to prevent tumour initiation. However, established tumours exploit autophagy to survive cellular stresses in the hostile tumour microenvironment. This can lead to therapy resistance, one of the biggest challenges facing current anti-cancer approaches. Autophagy modulation is an exciting area of clinical development, attempting to harness this fundamental process as an anti-cancer strategy. Autophagy induction could potentially prevent tumour formation and enhance anti-cancer immune responses. In addition, drug-induced autophagy could be used to kill cancer cells, particularly those in which the apoptotic machinery is defective. Conversely, autophagy inhibition may help to sensitise resistant cancer cells to conventional chemotherapies and specifically target autophagy-addicted tumours. Currently, hydroxychloroquine is in phase I and II clinical trials in combination with several standard chemotherapies, whereas direct, deliberate autophagy induction remains to be tested clinically. More comprehensive understanding of the roles of autophagy throughout different stages of carcinogenesis has potential to guide development of novel therapeutic strategies to eradicate cancer cells.