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

Abstract

Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality globally, with 30%-40% of cases developing metastasis, mainly to the liver. Although immunotherapy has shown promise for CRC treatment, patients with CRC liver metastasis (CRLM) experience limited therapeutic benefits, potentially because of an immunosuppressive tumor microenvironment (TME). Thus, an urgent need exists to identify the key players that drive CRLM and potentiate immunotherapeutic resistance. Herein, 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 (CAFs) through activation of β-catenin/HIF-1α-related transcription. CXCL12 promoted epithelial-mesenchymal transition of CRC 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 CRLM patients. 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 TME offer promising avenues for improving therapeutic outcomes in CRC patients with liver metastasis.