Scholarlink

Background <p>Dietary factors have been recognised as contributors to the etiology of colorectal cancer (CRC). Folate is a micronutrient of critical importance to human health, frequently utilized as a dietary supplement. Previous clinical evidence suggested that folate intake is associated with an increased risk of CRC. However, the underlying mechanisms remain unclear. Here, we report that folate supplementation significantly promotes CRC growth and is associated with functional exhaustion of cytotoxic CD8<sup>+</sup> T cell to enhance immune evasion.</p> Methods <p>Using subcutaneous and orthotopic colorectal cancer mouse models, we investigated the impact of folate on CRC progression. Flow cytometry, immunohistochemistry, immunofluorescence, Transwell assays, RNA sequencing, and ChIP-qPCR were employed to elucidate the role and underlying mechanisms of folate in modulating CD8<sup>+</sup> T cell function and recruitment within the tumor. By integrating dietary folate restriction with PD-1 monoclonal antibody therapy in subcutaneous tumor models, we further explored its effects in a preclinical setting.</p> Results <p>Our study indicates that folate directly impairs cytotoxic CD8<sup>+</sup> T cell function and promotes immune escape, thereby accelerating colorectal cancer progression. Mechanistically, folate enhances the expression of SLC19A1, which encodes the folate transporter RFC1, by promoting AKT phosphorylation. Elevated AKT phosphorylation activates the downstream NOTCH1 signaling pathway, leading to a T cell exhaustion phenotype. Meanwhile, folate in the tumor microenvironment suppresses PBX3 expression in CRC cells, thereby reducing CCL5 transcription and impeding CD8<sup>+</sup> T cell recruitment. Furthermore, in vivo dietary folate restriction enhances tumor control and synergizes with anti-PD-1 immunotherapy in CRC.</p> Conclusions <p>This preclinical study suggests that folate may facilitate CRC progression and immune evasion by impairing CD8<sup>+</sup> T cell recruitment and anti-tumor activity. These findings represent a proof-of-concept in mouse immunometabolism offering insights into potential mechanisms underlying folate-driven CRC progression and immune suppression. Broader implications for nutritional interventions or immunotherapy in patients remain speculative at this preclinical stage and would require further clinical investigation.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Folate promotes colorectal cancer progression by impairing CD8+ T cell function and recruitment via SLC19A1/p-AKT/NOTCH1 axis and CCL5 downregulation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月13日

查看全文
  • Shunjie Qing,
  • Yunyan Ling,
  • Yingjie Lai,
  • Yating Hu,
  • Yi Zhong,
  • Yuechen Liu,
  • Xiang Liu,
  • Yuan Fang,
  • Junying Qian,
  • Haijun Deng,
  • Yifeng Peng,
  • Dehua Wu,
  • Zhiyong Shen

摘要

Background

Dietary factors have been recognised as contributors to the etiology of colorectal cancer (CRC). Folate is a micronutrient of critical importance to human health, frequently utilized as a dietary supplement. Previous clinical evidence suggested that folate intake is associated with an increased risk of CRC. However, the underlying mechanisms remain unclear. Here, we report that folate supplementation significantly promotes CRC growth and is associated with functional exhaustion of cytotoxic CD8+ T cell to enhance immune evasion.

Methods

Using subcutaneous and orthotopic colorectal cancer mouse models, we investigated the impact of folate on CRC progression. Flow cytometry, immunohistochemistry, immunofluorescence, Transwell assays, RNA sequencing, and ChIP-qPCR were employed to elucidate the role and underlying mechanisms of folate in modulating CD8+ T cell function and recruitment within the tumor. By integrating dietary folate restriction with PD-1 monoclonal antibody therapy in subcutaneous tumor models, we further explored its effects in a preclinical setting.

Results

Our study indicates that folate directly impairs cytotoxic CD8+ T cell function and promotes immune escape, thereby accelerating colorectal cancer progression. Mechanistically, folate enhances the expression of SLC19A1, which encodes the folate transporter RFC1, by promoting AKT phosphorylation. Elevated AKT phosphorylation activates the downstream NOTCH1 signaling pathway, leading to a T cell exhaustion phenotype. Meanwhile, folate in the tumor microenvironment suppresses PBX3 expression in CRC cells, thereby reducing CCL5 transcription and impeding CD8+ T cell recruitment. Furthermore, in vivo dietary folate restriction enhances tumor control and synergizes with anti-PD-1 immunotherapy in CRC.

Conclusions

This preclinical study suggests that folate may facilitate CRC progression and immune evasion by impairing CD8+ T cell recruitment and anti-tumor activity. These findings represent a proof-of-concept in mouse immunometabolism offering insights into potential mechanisms underlying folate-driven CRC progression and immune suppression. Broader implications for nutritional interventions or immunotherapy in patients remain speculative at this preclinical stage and would require further clinical investigation.