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

Hepatocyte IRE1α–XBP1s signaling suppresses liver metastasis by limiting local metainflammation, and loss of hepatocyte IRE1α or XBP1 worsens disease via inflammatory monocyte accumulation.

• Why it matters: Tumor-promoting roles of IRE1α–XBP1s are known, but how this pathway shapes metastasis through non-cell-autonomous effects on the inflammatory microenvironment is unclear.
• What they did: In mice, hepatocyte-specific genetic ablation of IRE1α or XBP1 increases inflammatory monocytes; the effect is linked to a non-canonical FoxO1–glutamine synthetase pathway that enables glutamine secretion supporting IM fitness.
• The result: Restoring hepatocyte XBP1s or blocking glutamine metabolism reduces inflammatory monocytes and mitigates progression, and patient survival with liver metastases is positively correlated with hepatocyte XBP1s expression.

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