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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      This study identified two distinct TAM populations:\n                      <jats:italic>SPP1<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      and\n                      <jats:italic>SEPP1<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      TAMs.\n                      <jats:italic>SPP1<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      TAMs, associated with angiogenesis, immune evasion, and liver metastasis, were linked to poorer prognosis. This population exhibited tissue-specific differentiation trajectories and comprised two metabolic subtypes: a glycolytic\n                      <jats:italic>ATP5F1E<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      subtype enriched in primary tumors and lymph nodes, and an oxidative phosphorylation-dominant\n                      <jats:italic>MT-CO1<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      subtype specific to liver metastases. Spatially,\n                      <jats:italic>MT-CO1<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      <jats:italic>SPP1<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      TAMs localized to oxygen-rich invasive margins, while\n                      <jats:italic>ATP5F1E<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      <jats:italic>SPP1<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      TAMs resided in hypoxic tumor cores. Functionally,\n                      <jats:italic>SPP1<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      TAMs drove\n                      <jats:italic>CD8<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      T-cell exhaustion and spatial exclusion. In preclinical models, combined regorafenib and anti-programmed cell death protein 1 therapy reduced\n                      <jats:italic>SPP1<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      TAM infiltration and suppressed tumor growth and metastasis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study delineates the spatial, developmental, and metabolic heterogeneity of\n                      <jats:italic>SPP1<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      TAMs in CRC, identifying\n                      <jats:italic>SPP1<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-014128","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T14:50:21Z","timestamp":1774450221000},"page":"e014128","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Targeting\n                    <i>SPP1<\/i>\n                    <sup>+<\/sup>\n                    TAMs associated with liver metastasis reverses immunosuppression and synergizes with immunotherapy in colorectal cancer"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6811-634X","authenticated-orcid":false,"given":"Yilin","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Gastroenterological Surgery, Peking University 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