Mitochondrial DNA mutations drive tumor heterogeneity in papillary thyroid carcinoma.

Tumor heterogeneity presents a major challenge to understanding cancer evolution and therapeutic resistance in thyroid cancer. While previous studies have focused on nuclear driver mutations, the role of mitochondrial DNA (mtDNA) alterations in this heterogeneity remains elusive. Through multi-regional whole-genome and transcriptome sequencing of aggressive papillary thyroid carcinoma (PTC), we reveal that mtDNA mutations exhibit significant spatial and evolutionary heterogeneity, contrasting with conserved nuclear drivers. High mtDNA mutation burden correlated with increased mitochondrial gene expression, tumor dedifferentiation, and immune pathway activation via damage-associated molecular pattern signaling. This burden further remodeled the tumor microenvironment (TME), favoring pro-inflammatory epithelial states over normal stromal populations. Clinically, these features were associated with reduced disease-free survival. Our findings identify mtDNA mutations as key contributors to heterogeneity and TME remodeling in PTC, suggesting mitochondrial mutational burden as a potential prognostic biomarker and therapeutic target.