Integrative single‐cell transcriptomic and metabolic profiling reveals lactate‐driven glycolytic reprogramming and histone lactylation in colorectal cancer liver metastasis

Metabolic reprogramming and immune evasion are hallmarks of cancer metastasis, but how tumor metabolism shapes the immune microenvironment during colorectal cancer (CRC) liver metastasis remains poorly understood. The role of E-cadherin (CDH1) beyond cell adhesion is unexplored. We integrated single-cell RNA sequencing, pseudotime trajectory inference, and in vivo/in vitro functional assays in primary and liver-metastatic CRC models. CellChat was used to map intercellular communication. Histone lactylation, ADAM10 activation, and CDH1 shedding were validated by biochemical and immunohistochemical assays. PGK1-driven glycolysis is upregulated in liver metastases and promotes metastatic progression. Elevated lactate induces histone H3K18 lactylation, activating ADAM10 expression. ADAM10 cleaves CDH1, releasing its soluble ectodomain. This fragment acts as a ligand for KLRG1 on T cells, driving exhaustion and immunosuppression. Cell-cell communication analysis confirmed CDH1-KLRG1 as a top differentially activated pathway in metastasis. Functionally, targeting PGK1 or blocking CDH1 shedding inhibits liver metastasis and restores T-cell function. We identify a metabolic-epigenetic-immune axis in which tumor glycolysis reprograms immunity via lactate-induced CDH1 shedding. Soluble CDH1 functions as an immunomodulatory signal, linking metabolic activity to T-cell exhaustion. This redefines CDH1 as a dual-function molecule and reveals actionable targets for metastatic CRC. © 2026 The Pathological Society of Great Britain and Ireland.