SPP1 Drives Colorectal Cancer Liver Metastasis and Immunotherapy Resistance by Stimulating CXCL12 Production in Cancer-Associated Fibroblasts.

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.