Spatial multiomics reveals irreversible electroporation-induced immuno-metabolic characteristics of the inflammatory margin in liver cancer

Although irreversible electroporation (IRE) is an approved ablation therapy for liver cancer, the border of the IRE-induced inflammatory margin (IM) remains poorly defined, posing a challenge for investigating IRE-specific immune and metabolic alterations within this area. To address this, we employed a male C57BL/6 orthotopic liver cancer model and integrated spatial transcriptomics, spatial metabolomics, single-cell RNA sequencing, and cytometry by time-of-flight (CyTOF). This multiomics approach enabled precise spatial mapping of the IM and revealed a pronounced infiltration of Ly6ClowPD-L1hi that phenotypically resemble lipid-associated macrophages (LAMs). Further analysis uncovered profound lipid metabolic reprogramming within the IM, including biosynthesis of unsaturated fatty acids, arachidonic acid and sphingolipid metabolism, which appears to sustain the immunosuppressive phenotype of LAMs. Collectively, our study uncovers an IRE-specific immunosuppressive microenvironment in the IM and propose potential metabolic targets that might be effectively combined with IRE to improve therapeutic outcomes. Multiomics reveal an irreversible electroporation-specific immunosuppressive microenvironment within the inflammatory margin, maintained by lipid metabolic reprogramming, suggesting combinatory therapeutic targets.