Tumor metastasis co-opts liver hematopoiesis to promote immunosuppression

Cancer-associated hematopoietic abnormalities contribute to systemic immunosuppression. However, whether tumors can initiate localized extramedullary hematopoiesis to suppress antitumor immunity remains unclear. In this study, 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 C-C motif chemokine receptor 1 (CCR1) signaling. Although LM-HSCs retain self-renewal and multipotency, cAMP response element–binding protein (CREB) activation skews their differentiation toward the myeloid lineage, particularly annexin A1–positive (ANXA1 + ) immature neutrophils. These neutrophils produce glucocorticoids, which activate glucocorticoid receptor signaling in a paracrine manner and induce immune checkpoint receptor expression and functional anergy in CD8 + T and natural killer cells. Collectively, these findings suggest that liver metastases reprograms hepatic hematopoiesis to promote immunosuppression.