SPP1 Drives Colorectal Cancer Liver Metastasis and Immunotherapy Resistance - Mechanistic study of CXCL12 production in cancer-associated fibroblasts

Sep 22, 2026

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Colorectal cancer frequently progresses to liver metastasis, while immunotherapy in colorectal cancer liver metastasis (CRLM) is limited by an immunosuppressive tumor microenvironment. This study models CRLM liver metastatic cells and screens CRLM-related RNA expression profiles using spatial transcriptomic sequencing and single-cell analysis. SPP1 is upregulated and promotes immunotherapeutic resistance by stimulating cancer-associated fibroblast CXCL12 production via β-catenin/HIF1α-linked transcriptional activation. CXCL12 drives epithelial–mesenchymal transition yet suppresses CD8+ T-cell infiltration, and CXCL12 or SPP1 blockade restores anti–PD-1 efficacy. Elevated SPP1 and CXCL12 correlate with resistance in CRLM patients, supporting the SPP1/CXCL12 axis as target and biomarker for precise cancer immunotherapy.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages22

Reading Time55 min

AccessFree to download

Introduction

SPP1-mediated immunosuppressive tumor microenvironment and CRLM background

Significance

Potential therapeutic strategies and biomarker value

SPP1 Drives Colorectal Cancer Liver Metastasis and Immunotherapy Resistance by Stimulating CXCL12 Production in Cancer-Associated Fibroblasts Shengde Liu1, Zizhen Zhang1, Zhenghang Wang1,2, Cheng Liu1, Guanghao Liang3,4, Ting Xu1, Zhiwei Li1, Xiaorui Duan1, Gehan Xu1, Xujiao Feng1, Qin Feng2, Qi Wang5, Dali Han3,4, Cheng Zhang6, Jian Li6, and Lin Shen6 | | | A | | B | S | | T | R | | A | | C | T | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | 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. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China. 2 Department of Digestive Oncology, Peking University Cancer Hospital (Inner Mongolia Campus)/Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China. 3China National Center for Bioinformation, Beijing, China. 4University of Chinese Academy of

FAQs

What role does SPP1 play in colorectal cancer liver metastasis (CRLM)?

SPP1 is upregulated in CRLM and supports an immunosuppressive tumor microenvironment that promotes liver metastasis and immunotherapy resistance.

How does SPP1 increase immunotherapy resistance mechanistically?

SPP1 stimulates CXCL12 production in cancer-associated fibroblasts through β-catenin/HIF1α-related transcriptional activation.

How can resistance to anti–PD-1 therapy be improved based on the findings?

Blocking CXCL12 signaling or targeting SPP1 markedly activates intratumoral CD8+ T-cell infiltration and enhances the efficacy of anti–PD-1 antibody treatment.

Sep 22, 2026

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