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Background Liver metastasis is a common and fatal event for patients with pancreatic ductal adenocarcinoma (PDAC). Dysregulated mitochondrial dynamics reshape biological processes, including metabolism reprogramming, which disrupts immune cell function and promotes metastatic progression.Objective To identify key drivers that reprogramme PDAC mitochondrial function and its role in remodelling the immunosuppressive tumour microenvironment (TME) during PDAC liver colonisation.Design Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) loss-of-function screening, in vivo mouse model screening and in vitro anoikis-resistant cell selection were employed to identify key drivers during PDAC liver colonisation. PDAC organoids, metabolic flux analysis, single-cell RNA sequencing, spatial metabolomics and glutathione S-transferase (GST) pull-down assay were used to explore the regulation of mitochondrial fission process protein 1 (MTFP1) on PDAC liver colonisation and unravel the underlying mechanism.Results We revealed MTFP1, a protein that plays an important role in cell viability and mitochondrial dynamics, as a driver of PDAC liver colonisation. Mechanistically, MTFP1 is recognised as a novel ATP synthase modulator through its interaction with numerous ATP synthase subunits, thereby enhancing oxidative phosphorylation (OXPHOS). Increased mitochondrial fission and subsequent redox signalling (ROS production) upregulates solute carrier family A1 member 5 (SLC1A5) expression by activating the PI3K/AKT/c-MYC pathway, competing for glutamine uptake and impaired antitumour responses of CD8 + T cells. By performing virtual screening, we identified KPT 9274 (ATG-019) as an effective inhibitor of MTFP1. Limitation of glutamine uptake in PDAC cells or MTFP1 inhibition reverses the immunosuppressive TME and reduces liver colonisation of PDAC.Conclusion Our data demonstrate that the enhanced MTFP1 expression leads to an upregulated glutamine-OXPHOS axis in PDAC liver colonisation. This metabolic shift is triggered by the ROS/PI3K/AKT/c-MYC/SLC1A5 pathway. Targeting MTFP1 may be a potential therapeutic strategy for PDAC patients with liver metastasis.