ENO2 drives tumor cell-induced M2 macrophage polarization to promote colorectal cancer liver metastasis

Sep 22, 2026

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Liver metastasis is the leading cause of death in colorectal cancer, yet the tumor signals that initiate immune remodeling remain unclear. Single-cell RNA sequencing of primary tumors, adjacent tissues, and liver metastases revealed enrichment of Enolase 2 (ENO2)-expressing cancer cells in metastatic patients. Functional and mechanistic studies show ENO2 directly binds MIF in cancer cells, stabilizing MIF and activating MIF signaling to drive M2 macrophage polarization, promoting colorectal cancer liver metastasis. Organoid and in vivo validation identifies ENO2 as essential, with pyrithioxin reducing metastatic burden.

LanguageEnglish

CategoryHealthcare

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Pages13

Reading Time33 min

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Introduction

Tumor immune microenvironment in colorectal liver metastasis

Roles of tumor-associated macrophages and limitations of current therapies

Unresolved question: tumor-derived signals driving M2 reprogramming

Signal Transduction [and Targeted Therapy](and Targeted Therapy www.nature.com/sigtrans)[ www.nature.com/sigtrans](and Targeted Therapy www.nature.com/sigtrans) ENO2 drives tumor cell-induced M2 macrophage polarization to promote colorectal cancer liver metastasis Junwei Tang1,2, Zhihao Chen 1,2, Dongsheng Zhang 1,2, Kangpeng Jin 1,2, Hengjie Xu1,2, Chuanxin Tian 1,2, Jinling Duan3,4, Sheng Yang 1,2, Qingyang Sun 1,2, Yifei Feng1,2, Xiaowei Wang 1,2,5 ✉, Dan Xie 3,4 ✉ and Yueming Sun 1,2,3,6 ✉ | | Liver metastasis is the primary cause of mortality in colorectal cancer (CRC) patients. To decipher the underlying mechanisms, we performed single-cell RNA sequencing (scRNA-seq) on paired primary colorectal tumors, adjacent tissues and liver metastases from three CRC liver metastasis (CRLM) patients, alongside colorectal tumors and adjacent tissues from three non-metastatic CRC patients. Our analysis revealed a signiﬁcant enrichment of Enolase 2-expressing (ENO2⁺) cancer cells in CRLM patients compared to their non-metastatic counterparts. Functional characterization, supported by bioinformatics and murine models, demonstrated that ENO2⁺ cancer cells exhibit enhanced epithelial-mesenchymal transition (EMT) and are critical drivers of CRLM. Mechanistically, the ENO2 protein directly binds to macrophage migration inhibitory factor (MIF) within cancer cells, stabilizing MIF by inhibiting its C-terminus of Hsc70-Interacting Protein (CHIP)-mediated ubiquitination and degradation. This ENO2-MIF interaction activates MIF signaling, fostering robust tumor cell-macrophage crosstalk that promotes M2 macrophage polarization, which is validated by spatial transcriptomics showing the colocalization of ENO2⁺ cancer cells and M2 macrophages. Crucially, both organoid and in vivo models conﬁrmed that ENO2 in CRC cells is essential for inducing M2 macrophage polarization via the MIF pathway, thereby facilitating liver metastasis. Knockout of ENO2 signiﬁcantly suppressed tumor growth and liver metastasis in mouse models. An inhibitor of the ENO2-MIF interaction, pyrithioxin, can effectively reduce the burden of liver metastasis in mice. Collectively, our ﬁndings identify ENO2 as a key driver of CRLM by stabilizing MIF to orchestrate M2 macrophage polarization, highlighting the | | | | | | --- | --- | --- | --- | --- | --- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | ENO2-MIF axis as a | | promising therapeutic strategy for | CRLM. | | | | | Signal Transduction | and Targeted Therapy (2026)11:166 | ; | [https://doi.org/10.1038/s41392-026-02732-2](https://doi.org/10.1038/s41392-026-02732-2) | | | | | | | | | INTRODUCTION Colorectal cancer (CRC) ranks as the third most prevalent malignancy worldwide, with over 1.9 million new cases annually and mortality predominantly driven by distant metastasis.1 Among metastatic sites, the liver is the most common and lethal destination, accounting for >70% of CRC-related deaths.2 Current ﬁrst-line systemic therapies, including anti-epidermal growth factor receptor and anti-vascular endothelial growth factor targeted agents, have yielded limited survival beneﬁts in colorectal liver metastasis (CRLM) patients, especially for the vast majority with microsatellite stable (MSS) CRC, which exhibits primary resistance to single-agent immune checkpoint blockade.3 Despite multimodal advances, including surgical resection, systemic chemotherapy, and emerging immunotherapies, the 5-year survival for CRLM remains below 20% .4,5 This grim prognosis underscores an urgent need to decipher the molecular drivers of hepatic tropism and immune evasion, key biological features enabling metastatic outgrowth. The liver metastatic niche represents a dynamically remodeled ecosys

FAQs

What does the study identify as enriched in colorectal cancer liver metastasis (CRLM)?

ENO2-expressing (ENO2+) cancer cells are significantly enriched in CRLM patients compared with non-metastatic counterparts, based on single-cell RNA sequencing.

How does ENO2 promote M2 macrophage polarization?

ENO2 directly binds to macrophage migration inhibitory factor (MIF) in cancer cells, stabilizing MIF by preventing CHIP-mediated ubiquitination and degradation, which activates MIF signaling and supports tumor cell–macrophage crosstalk toward M2 polarization.

What experimental evidence supports ENO2’s role and therapeutic potential?

Organoid and in vivo models show ENO2 in CRC cells is required for inducing M2 macrophage polarization via the MIF pathway, while ENO2 knockout suppresses tumor growth and liver metastasis and pyrithioxin reduces liver metastatic burden in mice.

Sep 22, 2026

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