IDDF2026-ABS-0128 Progressive expansion of HIF-1 α -positive monocytes in the context of bone marrow priming during colorectal tumorigenesis

Background Our preliminary data suggest that HIF-1α-associated myeloid reprogramming emerges early and may be linked to bone marrow stress priming. To characterize systemic immune remodeling across colorectal tumorigenesis, define the dynamic changes in the monocyte lineage, and investigate whether tumor burden induces bone marrow priming associated with enhanced HIF-1α responsiveness. Methods Peripheral blood mononuclear cells from healthy controls (HC), patients with advanced adenoma (AA), and patients with early CRC were analyzed by cytometry by time-of-flight and single-cell RNA sequencing. Bone marrow, peripheral blood, and tumor tissues from naïve and MC38 tumor-bearing mice were analyzed by flow cytometry, quantitative PCR, DNase I hypersensitivity-qPCR, and Western blotting. Functional effects of HIF-1α-high myeloid cells were assessed in THP-1-based co-culture assays. Results High-dimensional immune profiling revealed progressive systemic immune remodeling from HC to AA to CRC, with a distinct HIF-1α-positive monocyte cluster showing significant stepwise expansion (IDDF2026-ABS-0128 Figure 1. Cytof profiling reveals systemic immune remodeling during colorectal tumorigenesis). The CRC-associated gene module was significantly enriched in HIF-1A signaling and glycolysis/gluconeogenesis pathways (IDDF2026-ABS-0128 Figure 2. Single-cell transcriptomic profiling identifies stage-dependent). High-resolution subclustering and pseudotime analysis further suggested progressive transition of CD14-positive monocytes toward an inflammatory CXCL8-positive terminal state, accompanied by activation of HIF-1α-related glycolytic programs (IDDF2026-ABS-0128 Figure 3. Differentiation trajectories and metabolic adaptation of HIF-1α-associated inflammatory myeloid states). In mouse models, tumor burden increased common monocyte progenitors and mature monocytes in bone marrow, enhanced chromatin accessibility at the Hif1a locus, and potentiated Hif1a induction after tumor supernatant stimulation. HIF-1α-high myeloid cells accumulated in peripheral blood and tumor tissues and promoted tumor cell proliferation and invasion in a HIF-1α-dependent manner (IDDF2026-ABS-0128 Figure 4. Tumor burden induces bone marrow myeloid priming and enhances HIF-1α-dependent tumor-promoting activity). Conclusions Systemic myeloid remodeling is initiated early during colorectal tumorigenesis and is characterized by progressive expansion of HIF-1α-positive monocytes. Tumor burden induces bone marrow priming that enhances HIF-1α responsiveness and may facilitate the generation of tumor-promoting inflammatory myeloid states. These findings support a bone marrow–periphery–tumor axis of myeloid reprogramming in CRC.