Tryptophan Metabolite Indole‐3‐Aldehyde Induces AhR and c‐MYC Degradation to Promote Tumor Immunogenicity

The role of tryptophan (Trp) and its metabolites in immune regulation is well-established, however, whether and how they regulate immunogenicity of tumor cells is not completely understood. In this study, a range of Trp metabolites are evaluated for their potential to modulate tumor immunogenicity using a co-culture assay with tumor cells and T cells. Indole-3-aldehyde (I3A) is identified as an indole derivative that significantly enhances tumor immunogenicity both in vitro and in vivo. This enhancement is attributed to the upregulation of antigen presentation and immunogenic molecules on tumor cells by I3A, thereby promoting their immunogenicity. Mechanistically, I3A induces the activation and degradation of Aryl hydrocarbon receptor (AhR), leading to increased expression of MHC-I molecules on tumor cell surfaces. Meantime, I3A induces rapid degradation of c-MYC in tumor cells and further enhances T cell activation. In mouse melanoma and lymphoma models, I3A demonstrates immune-dependent antitumor effects and enhances the efficacy of adoptive OT-I T cell therapy. Moreover, overexpression of the Trp metabolic enzyme interleukin-4-induced gene-1 (IL4I1) in tumor cells increases the intracellular level of I3A and enhances tumor immunogenicity. In summary, I3A is identified as a tumor immunogenicity inducer, which holds the potential to enhance antitumor immunotherapy efficacy.

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Publication Details

Journal
Advanced Science
Published
2025-06-29
DOI
https://doi.org/10.1002/advs.202409533
Citations
10
Primary Topic
Tryptophan and brain disorders
Type
article
Field-Weighted Citation Impact
5.78

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article

Tryptophan Metabolite Indole‐3‐Aldehyde Induces AhR and c‐MYC Degradation to Promote Tumor Immunogenicity

Xiaojun Xia, Jing Tan, Zixuan Guo, Hui Guo et al.
10 citations
Advanced Science
Tryptophan and brain disorders
5.78
article

Tryptophan Metabolite Indole‐3‐Aldehyde Induces AhR and c‐MYC Degradation to Promote Tumor Immunogenicity

Xiaojun Xia, Jing Tan, Zixuan Guo, Hui Guo, Zining Wang, Jin‐Xin Bei, Lei Cui, Feifei Xu, Hongxia Zhang, Tiantian Wang, Xiaojuan Wang, Peng Huang, C. Xie, Yongxiang Liu, Huan Jin, Jinyun Liu, Penghui Zhou, Huanling Zhang, Qi Zhao, Yanxun Lin
article en
10 citations

Abstract

The role of tryptophan (Trp) and its metabolites in immune regulation is well-established, however, whether and how they regulate immunogenicity of tumor cells is not completely understood. In this study, a range of Trp metabolites are evaluated for their potential to modulate tumor immunogenicity using a co-culture assay with tumor cells and T cells. Indole-3-aldehyde (I3A) is identified as an indole derivative that significantly enhances tumor immunogenicity both in vitro and in vivo. This enhancement is attributed to the upregulation of antigen presentation and immunogenic molecules on tumor cells by I3A, thereby promoting their immunogenicity. Mechanistically, I3A induces the activation and degradation of Aryl hydrocarbon receptor (AhR), leading to increased expression of MHC-I molecules on tumor cell surfaces. Meantime, I3A induces rapid degradation of c-MYC in tumor cells and further enhances T cell activation. In mouse melanoma and lymphoma models, I3A demonstrates immune-dependent antitumor effects and enhances the efficacy of adoptive OT-I T cell therapy. Moreover, overexpression of the Trp metabolic enzyme interleukin-4-induced gene-1 (IL4I1) in tumor cells increases the intracellular level of I3A and enhances tumor immunogenicity. In summary, I3A is identified as a tumor immunogenicity inducer, which holds the potential to enhance antitumor immunotherapy efficacy.

Advanced ScienceVol. 12(36)
Sun Yat-sen University (CN), Guangzhou First People's Hospital (CN), Sun Yat-sen University Cancer Center (CN), Third Affiliated Hospital of Sun Yat-sen University (CN), Southern Medical University (CN), Hainan Medical University (CN), Guangzhou Medical University (CN)
National Natural Science Foundation of China, Sun Yat-sen University, Fundamental Research Funds for the Central Universities
Good health and well-being
Openalex Percentile: Top 3%
Tryptophan and brain disorders
5.78
DOIOpen Access PDFOpenAlex
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