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IMPDH inhibitors upregulate PD-L1 in cancer cells without impairing immune checkpoint inhibitor efficacy

Acta Pharmacologica Sinica volume 46, pages 1058–1067 (2025)Cite this article

Abstract

Tumor cells are characterized by rapid proliferation. In order to provide purines for DNA and RNA synthesis, inosine 5’-monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo guanosine biosynthesis, is highly expressed in tumor cells. In this study we investigated whether IMPDH was involved in cancer immunoregulation. We revealed that the IMPDH inhibitors AVN944, MPA or ribavirin concentration-dependently upregulated PD-L1 expression in non-small cell lung cancer cell line NCI-H292. This effect was reproduced in other non-small cell lung cancer cell lines H460, H1299 and HCC827, colon cancer cell lines HT29, RKO and HCT116, as well as kidney cancer cell line Huh7. In NCI-H292 cells, we clarified that IMPDH inhibitors increased CD274 mRNA levels by enhancing CD274 mRNA stability. IMPDH inhibitors improved the affinity of the ARE-binding protein HuR for CD274 mRNA, thereby stabilizing CD274 mRNA. Guanosine supplementation abolished the IMPDH inhibitor-induced increase in PD-L1 expression. In CT26 and EMT6 tumor models used for ICIs based studies, we showed that despite its immunosuppressive properties, the IMPDH inhibitor mycophenolate mofetil did not reduce the clinical response of checkpoint inhibitors, representing an important clinical observation given that this class of drugs is approved for use in multiple diseases. We conclude that PD-L1 induction contributes to the immunosuppressive effect of IMPDH inhibitors. Furthermore, the IMPDH inhibitor mycophenolate mofetil does not antagonize immune checkpoint blockade.

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Fig. 1: IMPDH inhibitors upregulate PD-L1 expression on tumor cells.
Fig. 2: Guanosine supplementation abrogates the effect of IMPDH inhibitors on PD-L1 expression.
Fig. 3: IMPDH inhibitors improve CD274 mRNA stability.
Fig. 4: HuR is involved in IMPDH inhibitor-modulated CD274 mRNA stability.
Fig. 5: The antitumor effects of immune checkpoint blockade are not affected by the IMPDH inhibitor.
Fig. 6: Schematic of the effect of IMPDH inhibitors on stabilizing the CD274 mRNA.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82330114 to QJH, and No. 82273949 to LD).

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Authors and Affiliations

  1. Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Ming-ming Zheng, Jia-yi Li, Hong-jie Guo, Jie Zhang, Long-sheng Wang, Ke-fan Jiang, Hong-hai Wu, Qiao-jun He, Ling Ding & Bo Yang

  2. The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310018, China

    Qiao-jun He & Bo Yang

  3. Cancer Center of Zhejiang University, Hangzhou, 310058, China

    Qiao-jun He

  4. Nanhu Brain-Computer Interface Institute, Hangzhou, 311100, China

    Ling Ding

  5. School of Medicine, Hangzhou City University, Hangzhou, 310015, China

    Bo Yang

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  1. Ming-ming Zheng
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Contributions

MMZ contributed to the design, performed experiments and wrote the manuscript; JYL, HJG, JZ, LSW, KFJ, HHW and QJH contributed to the acquisition of the work, performed the statistical analysis and revised the article; LD and BY contributed to the conception of the work and provided project supervision.

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Correspondence to Ling Ding or Bo Yang.

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Zheng, Mm., Li, Jy., Guo, Hj. et al. IMPDH inhibitors upregulate PD-L1 in cancer cells without impairing immune checkpoint inhibitor efficacy. Acta Pharmacol Sin 46, 1058–1067 (2025). https://doi.org/10.1038/s41401-024-01411-8

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