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Background <p>The colorectal cancer (CRC) tumor microenvironment contains diverse myeloid populations that critically regulate antitumor immunity and therapeutic response. Tumor-associated macrophages are key regulators of macrophage–T-cell crosstalk within the CRC microenvironment. This study aimed to investigate the antitumor effects of Ethyl caffeate (EC) and determine whether EC modulates macrophage-associated immune remodeling in CRC.</p> Methods <p>Public single-cell RNA sequencing data from CRC tissues were analyzed to characterize myeloid infiltration, macrophage heterogeneity, Cell-cell communication, pseudotime trajectories, and macrophage-associated prognostic signatures. RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were used to evaluate the effects of EC on macrophage viability and polarization in vitro. An immunogenic syngeneic MC38 CRC model was established in C57BL/6 mice to assess the antitumor activity of EC. Flow cytometry was used to quantify tumor infiltrating macrophages, CD86⁺ M1-like macrophages, CD8⁺ T cells, Granzyme B expression, and PD-1 expression. Clodronate liposome-mediated macrophage depletion was performed to determine whether the antitumor effect of EC was macrophage dependent.</p> Results <p>Single-cell analysis revealed extensive myeloid infiltration and marked TAM heterogeneity in CRC. State-specific analyses identified CXCL9/CXCL10 IFN-responsive TAMs as a transitional immune activating population closely associated with CXCL10-CD8<sup>+</sup> T-cell immune signatures. Macrophage-derived gene signatures were associated with overall survival in the TCGA-COAD/READ cohort. EC showed limited cytotoxicity at 30 and 60 µM and promoted macrophage polarization toward an M1-like antitumor phenotype in RAW264.7 cells and BMDMs. In the immunogenic MC38 syngeneic CRC model, EC treatment significantly suppressed tumor growth, reducing tumor volume by 31.3% ± 10.0% at 25&#xa0;mg/kg and 46.6% ± 13.5% at 50&#xa0;mg/kg. EC increased CD86⁺ inflammatory macrophage-associated activation, enhanced CD8⁺ T-cell infiltration, increased Granzyme B expression, and reduced PD-1 expression on tumor infiltrating CD8⁺ T cells, suggesting enhanced CD8⁺ T-cell cytotoxic activation. Macrophage depletion largely attenuated the antitumor effect of EC.</p> Conclusions <p>EC suppresses colorectal tumor growth at least partly through macrophage-dependent immune remodeling. These findings identify EC as a potential macrophage-reprogramming compound that enhances CD8⁺ T-cell antitumor immunity in CRC.</p>

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Ethyl caffeate reprograms tumor-associated macrophages to enhance CD8+ T-cell immunity in colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月6日

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  • Zhixian Bao,
  • Jie Gao,
  • Xinhong Cheng,
  • Wenwen Yang,
  • Xiaomei Ma,
  • Rui Ji

摘要

Background

The colorectal cancer (CRC) tumor microenvironment contains diverse myeloid populations that critically regulate antitumor immunity and therapeutic response. Tumor-associated macrophages are key regulators of macrophage–T-cell crosstalk within the CRC microenvironment. This study aimed to investigate the antitumor effects of Ethyl caffeate (EC) and determine whether EC modulates macrophage-associated immune remodeling in CRC.

Methods

Public single-cell RNA sequencing data from CRC tissues were analyzed to characterize myeloid infiltration, macrophage heterogeneity, Cell-cell communication, pseudotime trajectories, and macrophage-associated prognostic signatures. RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were used to evaluate the effects of EC on macrophage viability and polarization in vitro. An immunogenic syngeneic MC38 CRC model was established in C57BL/6 mice to assess the antitumor activity of EC. Flow cytometry was used to quantify tumor infiltrating macrophages, CD86⁺ M1-like macrophages, CD8⁺ T cells, Granzyme B expression, and PD-1 expression. Clodronate liposome-mediated macrophage depletion was performed to determine whether the antitumor effect of EC was macrophage dependent.

Results

Single-cell analysis revealed extensive myeloid infiltration and marked TAM heterogeneity in CRC. State-specific analyses identified CXCL9/CXCL10 IFN-responsive TAMs as a transitional immune activating population closely associated with CXCL10-CD8+ T-cell immune signatures. Macrophage-derived gene signatures were associated with overall survival in the TCGA-COAD/READ cohort. EC showed limited cytotoxicity at 30 and 60 µM and promoted macrophage polarization toward an M1-like antitumor phenotype in RAW264.7 cells and BMDMs. In the immunogenic MC38 syngeneic CRC model, EC treatment significantly suppressed tumor growth, reducing tumor volume by 31.3% ± 10.0% at 25 mg/kg and 46.6% ± 13.5% at 50 mg/kg. EC increased CD86⁺ inflammatory macrophage-associated activation, enhanced CD8⁺ T-cell infiltration, increased Granzyme B expression, and reduced PD-1 expression on tumor infiltrating CD8⁺ T cells, suggesting enhanced CD8⁺ T-cell cytotoxic activation. Macrophage depletion largely attenuated the antitumor effect of EC.

Conclusions

EC suppresses colorectal tumor growth at least partly through macrophage-dependent immune remodeling. These findings identify EC as a potential macrophage-reprogramming compound that enhances CD8⁺ T-cell antitumor immunity in CRC.