CXCL8⁺HIF-1α⁺ macrophages define a disease-associated myeloid state during colorectal tumorigenesis.

Tumor-associated myeloid alterations extend beyond the local microenvironment and involve systemic changes in myeloid development and circulating monocytes. However, how these systemic changes are coordinated with macrophage reprogramming during colorectal tumorigenesis remains unclear. Here, we identified coordinated HIF-1α-associated changes across the monocyte-macrophage compartment in advanced adenoma and early colorectal cancer. Circulating HIF-1α⁺ monocytes were prominently altered in advanced adenoma, whereas colorectal tissues accumulated CXCL8⁺HIF-1α⁺ macrophages with enhanced glycolytic programs. In tumor-bearing mice, common monocyte progenitors and mature monocytes expanded together with HIF-1α⁺ myeloid cells, and macrophages acquired heightened HIF-1α responsiveness to tumor-derived signals. Functional perturbation further demonstrated that macrophage HIF-1α promoted tumor-cell survival, proliferation, and invasion. These findings define the systemic monocytic remodeling and HIF-1α-associated protumor macrophage activity as coordinated features of the myeloid response during colorectal tumorigenesis.