This study reveals that SPP1 promotes colorectal cancer liver metastasis and induces resistance to immunotherapy by activating CXCL12 expression in CAFs, offering new strategies for precision therapy targeting the SPP1/CXCL12 axis.
Literature Overview
This paper, 'SPP1 Drives Colorectal Cancer Liver Metastasis and Immunotherapy Resistance by Stimulating CXCL12 Production in Cancer-Associated Fibroblasts,' published in the journal Cancer Research, reviews and summarizes the role of SPP1 in colorectal cancer liver metastasis and its impact on immunotherapy resistance. The research team established a highly metastatic LoVo cell line and combined spatial transcriptome sequencing with single-cell analysis to identify significant upregulation of SPP1 in colorectal liver metastasis tissues. Further investigation revealed that SPP1 stimulates CAFs to secrete CXCL12 by activating β-catenin/HIF1α-associated transcription, thereby inducing epithelial-mesenchymal transition of cancer cells and suppressing CD8+ T cell infiltration. In mouse models, the use of CXCL12 receptor antagonists or anti-SPP1 antibodies significantly restored T cell infiltration and enhanced the effectiveness of anti-PD-1 therapy. This study provides new biomarkers and potential therapeutic targets for immunotherapy of colorectal cancer liver metastasis.Background Knowledge
Colorectal cancer (CRC) is one of the most common malignancies worldwide, with approximately 30%-40% of patients eventually developing metastasis, predominantly to the liver. Although immunotherapy has shown remarkable efficacy in treating various cancers, CRC liver metastasis (CRLM) patients exhibit poor responses to immunotherapy, primarily due to an immunosuppressive tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), the most abundant stromal cell type in TME, can influence immune cell infiltration and promote tumor progression by secreting various growth factors, cytokines, and chemokines. SPP1 (Secreted phosphoprotein 1, also known as osteopontin) is a secreted phosphorylated glycoprotein implicated in immunosuppressive functions of tumor-associated macrophages (TAMs) in multiple cancers. SPP1-positive macrophages are associated with poor prognosis in CRC patients, but its specific mechanisms in liver metastasis and immunotherapy resistance remain unclear. This study focuses on the functional role of SPP1 in CRLM and its impact on immunotherapy resistance, integrating animal models, patient samples, and molecular mechanisms to provide novel targeting insights for CRC precision therapy.
Research Methods and Experiments
The research team established a highly metastatic LoVo cell line (LoVo-HM) through in vivo serial passage and used bulk RNA-seq to identify gene expression changes associated with CRLM. Spatial transcriptomic and single-cell analyses revealed significant upregulation of SPP1 in CRLM. Western blot, ELISA, and immunohistochemistry were used to examine SPP1 protein expression in patient tissues. The study further constructed SPP1-overexpressing and SPP1-knockdown cell lines to assess its effects on cell migration, invasion, and epithelial-mesenchymal transition. TUNEL, EdU, Transwell, and scratch assays were employed to evaluate SPP1's regulatory role in CAFs function. In mouse models, SPP1 overexpression or siRNA knockdown, combined with anti-PD-1 therapy and CXCL12 antagonists, were used to assess changes in the tumor microenvironment and therapeutic efficacy. Additionally, the role of the SPP1/CXCL12 axis in tumor infiltration and immune cell exclusion was validated using patient-derived organoids (PDOs) and PDX models.Key Conclusions and Perspectives
Research Significance and Prospects
This study, for the first time, uncovers the dual role of SPP1 in promoting liver metastasis and inducing immunotherapy resistance in CRC, providing experimental evidence for developing SPP1/CXCL12-targeted therapeutic strategies. Future studies could further explore the role of the SPP1/CXCL12 axis in other tumor metastases and evaluate its potential as a biomarker for immunotherapy. Integrating gene-edited animal models with organoid platforms will enable deeper insights into SPP1-mediated TME remodeling and facilitate the development of novel anti-SPP1 or anti-CXCL12 therapeutic antibodies.
Conclusion
Through multi-omics and functional validation, this study demonstrates that SPP1 promotes colorectal cancer liver metastasis and induces immunotherapy resistance by enhancing CXCL12 secretion from CAFs, thereby inhibiting CD8+ T cell infiltration. The research team validated in mouse models that targeting SPP1 or CXCL12 significantly enhances the efficacy of anti-PD-1 therapy, suggesting the SPP1/CXCL12 axis as a potential therapeutic target for colorectal liver metastasis. These findings provide new molecular insights for personalized immunotherapy in CRC patients and highlight the key role of CAFs in immune evasion. Future work could involve validating the conservation of this signaling axis across different metastatic sites using patient-derived organoids and humanized immune system mouse models, while also developing novel immunotherapeutic approaches based on SPP1 inhibition.
