Targeting Autophagy in Cancer: Recent Advances and Future Directions

Abstract

Autophagy, a multistep lysosomal degradation pathway that supports nutrient recycling and metabolic adaptation, has been implicated as a process that regulates cancer. Although autophagy induction may limit the development of tumors, evidence in mouse models demonstrates that autophagy inhibition can limit the growth of established tumors and improve response to cancer therapeutics. Certain cancer genotypes may be especially prone to autophagy inhibition. Different strategies for autophagy modulation may be needed depending on the cancer context. Here, we review new advances in the molecular control of autophagy, the role of selective autophagy in cancer, and the role of autophagy within the tumor microenvironment and tumor immunity. We also highlight clinical efforts to repurpose lysosomal inhibitors, such as hydroxychloroquine, as anticancer agents that block autophagy, as well as the development of more potent and specific autophagy inhibitors for cancer treatment, and review future directions for autophagy research. SIGNIFICANCE: Autophagy plays a complex role in cancer, but autophagy inhibition may be an effective therapeutic strategy in advanced cancer. A deeper understanding of autophagy within the tumor microenvironment has enabled the development of novel inhibitors and clinical trial strategies. Challenges and opportunities remain to identify patients most likely to benefit from this approach.

Figure 1.

The autophagy pathway. There are 7 steps in the autophagy pathway. Steps 1 and 2 prepare intracellular membranes to form AVs by enriching the membrane for phosphatidylinositol 3 phosphate (PI3P). This lipid enrichment supports a complex ubiquitin-like conjugation system that results in the conjugation of LC3 family members to the lipid phosphatidylethanolamine (PE) on emerging AVs (Step 3). LC3 serves as a docking site for cargo adaptors that enable cargo loading into the AV (Step 4). AV maturation (Step 5) is followed by AV–lysosomal fusion (Step 6). Autophagic flux is completed with cargo degradation and recycling of nutrients (Step 7). Enzymes in the pathway that could serve as targets for drug therapy in cancer are highlighted in red.

Figure 2.

The role of autophagy in host–tumor cell interactions. Nontumor cells within the tumor microenvironment and outside of the tumor undergo profound changes when autophagy is inhibited in a systemic manner. Evidence from a number of laboratories suggests that autophagy in host cells enables tumor growth in specific ways. Autophagy inhibition in host cells impairs the growth of tumor cells independently of impairment of tumor growth achieved by autophagy inhibition in the tumor cells themselves.