Autophagy–Circulating Tumor DNA Axis in Molecular Cancer Research: Emerging Mechanisms, Therapeutic Targeting, and Translational Opportunities

Autophagy is a self-degradative homeostatic mechanism that plays an important role in tumor viability, metabolic reprogramming, and drug resistance. Circulating tumor DNA (ctDNA) is fragmented DNA that comes from dying tumor cells and leaks out into the blood stream. ctDNA can now be measured through blood tests and is a non-invasive way to identify cancer. ctDNA has shown promise for early detection of cancer, prognosis, and monitoring treatment response in real time. There is emerging mechanistic evidence suggesting a potential relationship between autophagy and ctDNA dynamics which has been discussed as a new autophagy–ctDNA axis. Autophagy can affect ctDNA levels by promoting or suppressing apoptosis and necrosis of tumor cells. When autophagy is cytoprotective, less DNA would be shed into the bloodstream. When autophagy is inhibited or defective, more DNA would be released because of increased genomic instability. Stressors found within the tumor microenvironment (TME) like hypoxia, oxidative stress, and nutrient depletion can also induce autophagy and indirectly affect ctDNA. Targeting autophagy therapeutically with drugs that induce or inhibit autophagy such as chloroquine (CQ) or mechanistic target of rapamycin (mTOR) inhibitors can affect ctDNA concentrations. Although emerging mechanistic evidence suggests a potential relationship between autophagy and ctDNA dynamics, direct clinical studies validating this interaction remain lacking. Therefore, this review presents the autophagy–ctDNA relationship as a hypothetical and exploratory model that warrants further mechanistic and translational investigation in cancer development, therapeutic resistance, and clinical applications.