Translational Perspectives on Cell-Free Mitochondrial DNA as a Biomarker in Gynecological Cancers: Current Limitations and Future Research Directions

In recent years, liquid biopsy has emerged as a promising non-invasive strategy for the identification of tumor-derived biomarkers. Among circulating analytes, cell-free DNA (cfDNA), including both nuclear and mitochondrial fractions, has been extensively investigated in a variety of biological fluids for its potential applications in cancer diagnosis, disease monitoring, and prognostic stratification. Owing to its higher copy number per cell compared with nuclear DNA, mitochondrial DNA (mtDNA) is typically present at higher concentrations in body fluids and is therefore potentially detectable. Circulating cell-free mitochondrial DNA (cfmtDNA) is closely associated with pro-inflammatory signaling pathways and cellular damage responses, including apoptosis, necrosis, and neutrophil extracellular trap formation (NETosis). This review provides a comprehensive overview of the reported alterations of cfmtDNA in the most prevalent gynecological malignancies, namely ovarian and endometrial cancers, which are characterized by a chronic inflammatory microenvironment. We further critically assess the current evidence supporting cfmtDNA as a potential non-invasive biomarker in these malignancies, highlighting current limitations and future research directions.