ArticleCancer research2026
SPP1 Drives Colorectal Cancer Liver Metastasis and Immunotherapy Resistance by Stimulating CXCL12 Production in Cancer-Associated Fibroblasts.
Article in Cancer research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Cancer metastasis: biological mechanisms, therapeutic bottlenecks, and emerging interventions.Journal of hematology & oncology · 2026Review
- Integrative multi-omics profiling of insomnia-related molecular features reveals microbiome, immune, and therapy-relevant heterogeneity in colorectal cancer.Microbiology spectrum · 2026Article
- Characterization of SPP1 + macrophages and their correlation with resistance to neoadjuvant chemotherapy in colorectal cancer liver metastasis.Molecular biomedicine · 2026Article
- Evolution of SPP1Cell reports. Medicine · 2026Article
- Tumor stroma-immune interactions shape the immunosuppressive microenvironment and predict response to neoadjuvant chemoradiotherapy plus immunotherapy in rectal cancer.Journal for immunotherapy of cancer · 2026Observational
- SLC7A5 promotes colorectal cancer liver metastasis by reprogramming tryptophan metabolism through the Kyn/XANA‒AhR axis and reshaping the immune microenvironment.Clinical and translational medicine · 2026Article
- Concurrent genetic and non-genetic resistance mechanisms to KRAS inhibition in colorectal cancer.Cancer cell · 2026Article
- SPP1 promotes lymph node metastasis and malignant progression of head and neck squamous cell carcinoma by activating FAK-AKT signaling pathway.World journal of surgical oncology · 2026Article
- Exosome-mediated miR-4660 delivery inhibits OPN promoted hepatoma cells aggression through targeting LGALS3BP.Journal of cell communication and signaling · 2026Article
- Bidirectional crosstalk between cancer-associated fibroblasts and tumor immunity: shaping the microenvironment and response to immune checkpoint therapy.Experimental hematology & oncology · 2026Review
- SPP1 knockdown inhibits invasion, migration and paclitaxel-induced Epithelial-Mesenchymal Transition in Cervical Cancer Cells through the TGF-β/Akt/Snail pathway.Scientific reports · 2026Article
- Cytokines and cancer-associated fibroblasts.Journal of hematology & oncology · 2026Review
- Article
- Single-cell RNA sequencing reveals HMGA2 involvement in neoplastic aggressiveness and endothelial cell senescence in chondrosarcoma.Cell biology and toxicology · 2026Article
- Cancer-associated fibroblasts and immune escape-related genes serve as biological markers for the prognosis of colorectal cancer.Hereditas · 2026Article
- GALNT10 Affects O-Glycosylation of IGFBP7 to Promote Tumor Vascular Remodeling and Metastasis of Ovarian Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- TargetingJournal for immunotherapy of cancer · 2026Article
- Targeting sialic acid metabolism: a therapeutic strategy against gastric cancer driven by WZ35.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- Integrated single-cell and spatial transcriptomic analysis reveals mCAF-SPP1⁺ macrophage-T cell crosstalk shaping immunosuppressive niches in colorectal cancer liver metastasis.Journal of translational medicine · 2026Article
- Distinct and cooperative roles of host and tumor Osteopontin in colorectal cancer liver metastasis.bioRxiv : the preprint server for biology · 2026Article
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16 authors.
Funding
Abstract
Colorectal cancer remains a major cause of cancer-related morbidity and mortality globally, with 30% to 40% of cases developing metastasis, mainly to the liver. Although immunotherapy has shown promise for colorectal cancer treatment, patients with colorectal cancer liver metastasis (CRLM) experience limited therapeutic benefits, potentially because of an immunosuppressive tumor microenvironment. Thus, an urgent need exists to identify the key players that drive CRLM and potentiate immunotherapeutic resistance. In this study, we established liver metastatic cells through continuous passaging in vivo, allowing the screening of RNA expression profiles related to CRLM. A combination of spatial transcriptomic sequencing and single-cell analysis revealed a substantial upregulation of SPP1 expression and secretion in CRLM. SPP1 induced immunotherapeutic resistance by stimulating CXCL12 production by cancer-associated fibroblasts through activation of β-catenin/HIF1α-related transcription. CXCL12 promoted epithelial-mesenchymal transition of colorectal cancer cells but suppressed CD8+ T-cell infiltration. Treatment with a CXCL12 receptor antagonist or anti-SPP1 antibody markedly activated intratumoral CD8+ T-cell infiltration and enhanced the efficacy of anti-PD-1 antibody treatment. Elevated SPP1 and CXCL12 corresponded to immunotherapy resistance in patients with CRLM. Together, this study highlights the potential of the SPP1/CXCL12 axis as a target and a biomarker for precise cancer immunotherapy in CRLM. The intricate interactions within the tumor microenvironment offer promising avenues for improving therapeutic outcomes in patients with CRLM. SIGNIFICANCE: SPP1 orchestrates development of an immunosuppressive tumor microenvironment that supports liver metastasis of colorectal cancer cells, offering insights into potential strategies for improving immunotherapy efficacy in liver metastatic colorectal cancer.
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