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Review
. 2023 Nov 30;12(23):2742.
doi: 10.3390/cells12232742.

Unraveling the Intricacies of Autophagy and Mitophagy: Implications in Cancer Biology

Sunmi Lee  1 , Ji-Yoon Son  1 , Jinkyung Lee  2 , Heesun Cheong  1   2
Affiliations
Review

Unraveling the Intricacies of Autophagy and Mitophagy: Implications in Cancer Biology

Sunmi Lee et al. Cells. .

Abstract

Autophagy is an essential lysosome-mediated degradation pathway that maintains cellular homeostasis and viability in response to various intra- and extracellular stresses. Mitophagy is a type of autophagy that is involved in the intricate removal of dysfunctional mitochondria during conditions of metabolic stress. In this review, we describe the multifaceted roles of autophagy and mitophagy in normal physiology and the field of cancer biology. Autophagy and mitophagy exhibit dual context-dependent roles in cancer development, acting as tumor suppressors and promoters. We also discuss the important role of autophagy and mitophagy within the cancer microenvironment and how autophagy and mitophagy influence tumor host-cell interactions to overcome metabolic deficiencies and sustain the activity of cancer-associated fibroblasts (CAFs) in a stromal environment. Finally, we explore the dynamic interplay between autophagy and the immune response in tumors, indicating their potential as immunomodulatory targets in cancer therapy. As the field of autophagy and mitophagy continues to evolve, this comprehensive review provides insights into their important roles in cancer and cancer microenvironment.

Keywords: autophagy; cancer; cancer-associated fibroblasts (CAFs); mitophagy; tumor microenvironment (TME); tumor-associated immune cells.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A brief overview of autophagy and mitophagy processes.
Figure 2
Figure 2
The context-dependent role of autophagy in tumor progression. Autophagy/mitophagy in normal cells maintains cellular homeostasis by eliminating malfunctioning organelles, misfolded protein, and unnecessary cytoplasmic components. When autophagy is not carried out, accumulated cellular damage, such as genomic instability and inflammation, might initiate tumorigenesis (left). On the other hand, autophagy/mitophagy in tumor cells promotes cell growth and survival by recycling degraded proteins and damaged organelles as energy sources, which results in advanced malignancy. When autophagy is not carried out in tumor cells, no further tumor progression occurs (right).
Figure 3
Figure 3
Illustration depicting how autophagy in various host cells within the tumor microenvironment (TME) mediates crosstalk that supports tumor promotion. Autophagy inhibition affects the anti-tumorigenic roles of diverse host cells in the TME. In host stromal cells, such as cancer-associated fibroblasts (CAFs), autophagy promotes the generation of cellular metabolites, including amino acids derived from macromolecule degradation, supporting tumor cell growth and survival. Additionally, CAFs generate exosomes in an LC3/GABARAP-mediated manner, which are secreted and contain pro-tumorigenic growth factors and cytokines, further promoting tumor cell proliferation. Autophagy-driven pro-collagen degradation and proline production also contribute to extracellular matrix (ECM) production, facilitating tumor proliferation. In host immune cells adjacent to tumors, autophagy plays a role in the degradation of MHC class I mediated by NBR1, an autophagy receptor, thereby inhibiting cytotoxic T cell-mediated tumor killing. Autophagy inhibition in dendritic cells (DCs) or cancer cells leads to increased MHC-I levels on the cell surface by preventing autophagic degradation, thus supporting cytotoxic T cell-mediated cancer death. The black dotted line indicates a tumor-promoting effect, while the red line represents a tumor-suppressing effect. (MHC I; major histocompatibility complex I, TCR; T cell receptor, NBR1; neighbor of the Brca1 gene).
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