Hepatocyte IRE1α–XBP1s axis prevents pro-metastatic niche formation through metabolic rewiring of inflammatory monocytes

Inositol-requiring enzyme 1α (IRE1α) and the downstream spliced form of X-Box Binding Protein 1 (XBP1s) have been identified as tumor promotors. However, how IRE1α–XBP1s signaling affects tumor progression in a non-cell autonomous manner remains unclear. Here we show that the hepatocyte IRE1α–XBP1s axis unexpectedly inhibits liver metastasis by confining local metainflammation. Genetic ablation of IRE1α or XBP1 in mouse hepatocytes exacerbates liver metastasis due to the accumulation of inflammatory monocytes (IMs). Mechanistically, a non-canonical Forkhead box O1 (FoxO1)-glutamine synthetase (GS) pathway endows the IRE1α- or XBP1-null hepatocytes with the metabolic activity to secrete glutamine, which is necessary and sufficient for IM fitness. Reintroduction of hepatocyte XBP1s or blockade of glutamine metabolism effectively reduces IMs and mitigates disease progression. Importantly, clinical patient survival with liver metastases positively correlates with hepatocyte XBP1s expression. Our study defines a paradigm of hepatocyte–IM interaction that can be leveraged to treat liver metastasis.