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Cellular and Molecular Biology

Targeting gut microbiota and arginase boosts MEK inhibitors’ enhancement of antitumour immunity via MHC-I upregulation in colorectal cancer

British Journal of Cancer volume 133, pages 809–822 (2025)Cite this article

Subjects

Abstract

Background

Elevating major histocompatibility complex class I (MHC-I) levels in tumour cells can boost antitumour immunity and enhance immunotherapy for colorectal cancer (CRC). Screening an FDA-approved drug library showed that MEK inhibitors (MEKis) significantly increase MHC-I expression in CRC cells, though the mechanisms and antitumour effects of MEKis, as well as their impact on gut microbiota, remain unclear.

Methods

Dual-luciferase reporter system was employed to screen MHC-I inducers. MHC-I expression was analysed using qRT-PCR, flow cytometry, and western blot. OT-I TCR transgenic mice, subcutaneous mouse tumour models, RNA-seq, and ChIP-qPCR were used to identify the underlying mechanism. Gut microbiota was depleted using antibiotics cocktail and analysed via Shotgun sequencing, 16S rRNA sequencing and nontargeted metabolomic sequencing.

Results

MEKis, particularly cobimetinib, increased MHC-I expression by inhibiting PRMT5-mediated repression of NLRC5, boosting CD8+ T cell-mediated immunity and enhancing PD-L1 blockade efficacy. Cobimetinib also altered gut microbiota, reducing L-arginine via arginase production, which compromised antitumour immunity. Arginase inhibition or L-arginine supplementation restored immune responses.

Conclusions

This study uncovers a novel mechanism of MEKi-induced MHC-I expression and highlights the interplay between gut microbiota and antitumour immunity, providing insights for MEKi-based CRC immunotherapy.

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Fig. 1: MEK inhibitors increase the expression of MHC-I.
Fig. 2: Cobimetinib-induced MHC-I expression enhances CD8+ T cell-dependent antitumour immunity and increases anti-PD-L1 therapy efficacy.
Fig. 3: Cobimetinib increases MHC-I levels by increasing NLRC5 expression.
Fig. 4: Cobimetinib elevates NLRC5 and HLA-A expression by decreasing PRMT5 expression.
Fig. 5: The gut microbiota and metabolites regulate the antitumour effect of MEKis.
Fig. 6: L-Arginine supplementation enhances the antitumour immunity induced by MEKis.
Fig. 7: Inhibition of arginase production by the gut microbiota enhances the antitumour immunity induced by MEKis.

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Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Professor Wende Li from Guangdong Laboratory Animals Monitoring Institute for kindly providing OT-I mice.

Funding

This work was supported by National Natural Science Foundation of China (82172337); Guangdong Basic and Applied Basic Research Foundation (2021A1515012530, 2022A1515140001, 2023A1515012377); Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004); The Announcement and Recruitment Project of the Sixth Affiliated Hospital of Sun Yat-sen University (2022JBGS08); National Key Clinical Discipline.

Author information

Author notes

  1. These authors contributed equally: Jingdan Zhang, Haiyan Dong, Liumei Liang.

  2. These authors jointly supervised this work: Huanliang Liu, Xiangling Yang, Chuangyu Wen.

Authors and Affiliations

  1. Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Jingdan Zhang, Haiyan Dong, Liumei Liang, Limei Hu, Junxiong Chen, Weiqian Li, Jiaqi Liu, Yixi Su, Mengchen Shi, Yanchun Feng, Huanliang Liu & Xiangling Yang

  2. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Jingdan Zhang, Haiyan Dong, Liumei Liang, Limei Hu, Junxiong Chen, Weiqian Li, Jiaqi Liu, Yixi Su, Mengchen Shi, Yanchun Feng, Huanliang Liu & Xiangling Yang

  3. Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Jingdan Zhang, Haiyan Dong, Liumei Liang, Limei Hu, Junxiong Chen, Weiqian Li, Jiaqi Liu, Yixi Su, Mengchen Shi, Yanchun Feng, Huanliang Liu & Xiangling Yang

  4. Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Jingdan Zhang, Haiyan Dong, Liumei Liang, Limei Hu, Junxiong Chen, Weiqian Li, Jiaqi Liu, Yixi Su, Mengchen Shi, Yanchun Feng, Huanliang Liu & Xiangling Yang

  5. Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China

    Jingdan Zhang, Haiyan Dong, Liumei Liang, Limei Hu, Junxiong Chen, Weiqian Li, Jiaqi Liu, Yixi Su, Mengchen Shi, Yanchun Feng, Huanliang Liu & Xiangling Yang

  6. Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Junxiong Chen

  7. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA

    Emile Z. Naccasha & Chuangyu Wen

  8. Department of Molecular and Systems Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA

    Cara Lewis

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Contributions

JZ, HD and LL conducted the experiments, prepared the figures, drafted the manuscript. LH, JC and WL provided technical support and suggestions for the manuscript. JL, YS, MS and YF participated in the analysis and interpretation of data. EN and CL revised the manuscript. HL, XY and CW designed the work, supervised the project and revised the manuscript. All authors have read and approved the article.

Corresponding authors

Correspondence to Huanliang Liu, Xiangling Yang or Chuangyu Wen.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Written informed consent was obtained from the patients, and the protocol for using human blood samples was approved by the Institutional Review Board of the Sixth Affiliated Hospital of Sun Yat-sen University (2018ZSLYEC-008). The animal experiments in this study were evaluated and approved by the Institutional Animal Care and Use Committee (IACUC, NO: IACUC- 2022032701, 2021122201) of The Sixth Affiliated Hospital, Sun Yat‐sen University. All analyses were conducted in accordance with the Declaration of Helsinki.

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Zhang, J., Dong, H., Liang, L. et al. Targeting gut microbiota and arginase boosts MEK inhibitors’ enhancement of antitumour immunity via MHC-I upregulation in colorectal cancer. Br J Cancer 133, 809–822 (2025). https://doi.org/10.1038/s41416-025-03106-1

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