Pancreatic ductal adenocarcinoma (PDAC) is characterised by immune hypo-responsiveness due to its complex, immunosuppressive tumour microenvironment (TME). Mitochondrial metabolic reprogramming allows PDAC cells to shift between glycolysis and oxidative phosphorylation (OXPHOS), supporting energy production and cellular viability, thus promoting tumour progression and therapeutic resistance. Mitochondrial genes associated with PDAC were identified using SMR/HEIDI analysis combined with MRC IEU OpenGWAS and GTEx V8 pancreatic eQTL databases. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were used to explore cellular interactions and construct spatial interaction networks. Potential small-molecule compounds targeting the TME were identified through drug prediction and molecular docking. COA6 expression was silenced in SW1990 and PANC-1 cells to assess effects on cell proliferation, migration, invasion and apoptosis. COA6, a key gene in the OXPHOS pathway, was upregulated in PDAC tumours compared to normal tissues. Functional assays showed that COA6 overexpression enhanced proliferation, migration and chemoresistance of PDAC cells. COA6 modulates OXPHOS, influences the TME and promotes drug resistance in PDAC. It is a promising therapeutic target for improving clinical outcomes in PDAC patients. Further research is needed to develop COA6-targeted therapies.© 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.