Hepatic hematopoiesis hijacked by tumor metastasis promotes immunosuppression

However, whether tumors can initiate localized extramedullary hematopoiesis (EMH) to suppress anti-tumor immunity remains unclear. Here, we identify a distinct form of hepatic hematopoiesis driven by liver metastasis-associated hematopoietic stem cells (LM-HSCs).

Liver metastases establish ectopic periportal hematopoietic niches that recruit bone marrow HSCs through Kupffer cell-dependent CCR1 signaling. Although LM-HSCs retain self-renewal and multipotency, CREB activation skews their differentiation toward the myeloid lineage, particularly ANXA1⁺ immature neutrophils. These neutrophils produce glucocorticoids, which activate glucocorticoid receptor (GR) signaling in a paracrine manner and induce immune checkpoint receptor expression and functional anergy in CD8⁺ T and NK cells.