Targeting SPP1 + TAMs associated with liver metastasis reverses immunosuppression and synergizes with immunotherapy in colorectal cancer

BACKGROUND: Tumor-associated macrophages (TAMs) are critically involved in colorectal cancer (CRC) progression, yet their spatial and metabolic heterogeneity across primary and metastatic microenvironments remains poorly defined, limiting therapeutic development. METHODS: Integrated single-cell RNA sequencing was performed on 998,204 cells from a multicenter cohort encompassing primary CRC, adjacent normal tissue, liver and lymph node metastases, and peripheral blood. Computational analyses included uniform manifold approximation and projection (UMAP) clustering, pseudotime inference, RNA velocity, and CellChat. Findings were validated using multiplex immunohistochemistry, spatial transcriptomics, and in vivo preclinical models. RESULTS: TAM infiltration and suppressed tumor growth and metastasis. CONCLUSION: TAMs as key mediators of immunosuppression and metastasis. Targeting these populations with combination therapy effectively enhances antitumor immunity, presenting a novel translational strategy for CRC immunotherapy.