How does autophagy contribute to cancer healing?

Autophagy's Dual Role in Cancer: Context-Dependent Effects on Tumor Biology

Autophagy functions as a double-edged sword in cancer, acting as a tumor suppressor in early stages by preventing genomic instability, but promoting tumor survival and therapy resistance in established cancers by enabling stress tolerance and metabolic adaptation. 1

Tumor Suppression in Early Cancer Development

In the initial stages of tumorigenesis, autophagy prevents cancer development through several protective mechanisms:

• Autophagy genes (ATG5, BECN1) are frequently mono-allelically deleted or silenced in human tumors, creating an environment of increased oxidative stress that promotes DNA damage and genomic instability 2
• The process removes damaged organelles and misfolded proteins, preventing the accumulation of harmful cellular materials that could trigger malignant transformation 1
• Inhibition of autophagy in mitotic cells induces chromosomal instability, one of the hallmarks of cancer, leading to abnormal chromosomal segregation and formation of toroidal nuclei in daughter cells 1

Tumor Promotion in Advanced Cancer

Once tumors are established, autophagy shifts to a pro-survival mechanism that facilitates cancer progression:

• Cancer cells activate autophagy in response to metabolic stress and increased demands from rapid proliferation, using it to maintain energy production through recycling of cellular components 3, 4
• Autophagy-related stress tolerance enables tumor cell survival under hypoxic conditions, nutrient deprivation, and therapeutic pressure, promoting tumor growth and resistance to treatment 4, 2
• Advanced cancers become dependent on basal autophagy for survival, even though they maintain reduced levels compared to normal cells 2

Mechanism of Action in Cancer Cells

Autophagy supports cancer cell survival through specific molecular pathways:

• The lysosome-dependent degradation process recycles metabolic substrates, providing energy and building blocks during stress conditions such as nutrient deprivation 1
• Selective autophagy (mitophagy) eliminates impaired mitochondria, maintaining mitochondrial homeostasis critical for cancer cell metabolism 1
• Autophagy can promote cell death through autophagy-dependent ferroptosis (ADF), an iron-dependent pathway involving lipid peroxidation that selectively targets certain cancer cells, particularly those with oncogenic RAS mutations 1

Therapeutic Implications: Inhibition vs. Activation

The therapeutic strategy depends critically on cancer type, stage, and baseline autophagy levels:

When to Inhibit Autophagy:

• In established tumors where autophagy drives therapy resistance, inhibition restores chemosensitivity and enhances tumor cell death 4
• Chloroquine and hydroxychloroquine raise lysosomal pH, preventing autophagosome-lysosome fusion and blocking late-stage autophagy 1
• Multiple early phase clinical trials evaluate hydroxychloroquine combined with chemotherapy or targeted agents to overcome autophagy-mediated resistance 4

When to Activate Autophagy:

• In cancers where enhanced autophagy causes autophagy-mediated cell death, activation through anti-cancer drugs can be therapeutic 5
• Pharmacological induction of autophagy-dependent ferroptosis using erastin or RSL3 analogs holds promise as a cancer therapy strategy, particularly targeting the SLC7A11-GSH-GPX4 axis 1

Critical Caveats and Clinical Considerations

Several important factors determine autophagy's role in specific cancer contexts:

• The effect varies by tissue type, cancer origin, and tumor stage—what works in one cancer may be contraindicated in another 3, 5
• Basal autophagy levels must be determined before treatment initiation, as manipulation may either promote or hinder cancer growth depending on these baseline levels 5
• Current autophagy inhibitors like chloroquine lack specificity, creating a need for more potent and selective inhibitors for optimal therapeutic application 6, 4
• Circular RNAs (circRNAs) regulate autophagy in tissue-specific patterns, with some (circ-DNMT1) stimulating autophagy and increasing breast cancer proliferation, while others (ciRS-7) inhibit autophagy in esophageal cancer 1

The paradox remains that while tumor cells reduce autophagy levels, they never eliminate this pathway completely, maintaining dependence on residual autophagy for survival under metabolic stress. 2