Integrating spatial omics and single-cell mass spectrometry imaging reveals tumor-host metabolic interplay in hepatocellular carcinoma.

Metabolic crosstalk among diverse cellular populations contributes to shaping a competitive and symbiotic tumor microenvironment (TME) to influence cancer progression and immune responses, highlighting vulnerabilities that can be exploited for cancer therapy. Using a spatial multiomics platform to study the cell-specific metabolic spectrum in hepatocellular carcinoma (HCC), we map the metabolic interactions between different cells in the HCC TME and identify a unique tumor-immune-cancer-associated fibroblast (CAF) "interface" zone, where cell-cell interactions are enhanced and accompanied by significant upregulation of lactic acid and long-chain polyunsaturated fatty acids. Further combining single-cell mass spectrometry imaging of patient-derived tumor organoids, cocultured CAFs, and macrophages, we demonstrate that CAFs increase glycolysis and secrete lactic acid to the surrounding microenvironment to drive immunosuppressive macrophage M2 polarization. These findings facilitate the understanding of cancer-associated metabolic interactions in complex TME and provide clues for targeted clinical therapies.