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Cellular and Molecular Biology

Fasting-mimicking diet induces IFNβ secretion in tumor-associated macrophages via NRF1-mediated ubiquitin-dependent proteolysis of Trex1

British Journal of Cancer (2026)Cite this article

Subjects

Abstract

Background

Fasting-mimicking diet (FMD) is a safe and effective strategy in clinical oncology via metabolically restricting tumour growth and remodelling the immunity. To date, few studies have investigated the impact of on tumour-associated macrophages (TAMs), which are a crucial component of immune cells in the tumour microenvironment. Fasting can induce the ubiquitin-proteasome system (UPS) to regulate intracellular protein turnover homoeostasis, while Nuclear Factor Erythroid 2-like 1 (NRF1; encoded by the gene Nfe2l1), which controls proteasome gene transcription, may potentially be induced by fasting. However, whether NRF1 is induced by FMD/fasting, and how NRF1-mediated protein turnover works on TAMs remain unknown. This study investigated the hypothesis that FMD activates the anti-tumour immunity of TAMs by ubiquitinated protein metabolism.

Methods

Subcutaneous MC38 tumour models were established in WT and myeloid-specific NRF1 knockout (Mye-NFE2L1-/-) C57BL/6 mice, treated with FMD alone or combined with intraperitoneal Trex1 inhibitor (Trex1-IN-1). TAMs were isolated from tumour tissues using CD11b+ magnetic bead sorting. In vitro, bone marrow-derived macrophages (BMDMs) were co-cultured with MC38 in fasting medium, with MC38 proliferation assessed by CCK8 assay. BMDM-derived TAMs (B-TAMs) were induced by MC38 supernatant under fasting conditions. IFNβ levels in serum and cell supernatant were measured by ELISA. RNA-seq was performed to compare WT and Mye-NFE2L1-/- BMDMs under fasting conditions. Protein levels of cGAS-Sting pathway components, ubiquitinated proteins, and nuclear NRF1 were analysed by Western blot, while Trex1 ubiquitination was assessed by Co-IP. qPCR quantified IFNβ-related gene expression and mitochondrial DNA (mtDNA) copy number. Trex1-mitochondria colocalization was examined by immunofluorescence, and Trex1-bound mtDNA levels were determined by ChIP-qPCR.

Results

FMD/fasting triggers interferon-β (IFNβ) secretion in TAMs, which is driven by protein metabolism. In TAMs with FMD, an initial accumulation of ubiquitinated proteins occurs concomitantly with the induction of NRF1 in response to fasting-induced energy stress, leading to the ubiquitin/proteasome-dependent proteolysis of the three prime repair exonuclease 1 (Trex1) through UPS. Such a process engages type I interferon responses, which derepress the cGAS-Sting-IFNβ axis to promote anti-tumour effects of TAMs. In the absence of NRF1, Trex1 accumulates due to impaired UPS and binds to mtDNA, disrupting cGAS sensing of mtDNA to inhibit IFNβ secretion in TAMs, which attenuates anti-tumour effects of FMD/fasting.

Conclusion

In this study, we revealed for the first time that FMD/fasting coordinates NRF1-UPS and Trex1/Sting-mediated type I interferon responses in TAMs that contribute to suppressing tumour growth.

Graphical abstract: FMD upregulates the entry of NRF1 into the TAM nucleus to promote gene expression of proteasome subunits, which induces the ubiquitin/proteasome-dependent proteolysis of Trex1, leading to derepression of the cGAS-Sting-IFNβ axis. On the other hand, FMD triggers increasing of mtDNA in TAMs, promoting the cGAS-Sting-IFNβ axis to release IFNβ. In myeloid NRF1 knockout TAMs, transcriptional levels of proteasome subunits are reduced, resulting in impaired proteolysis of Trex1 and its subsequent accumulation during fasting. Then, Trex1 binds to mtDNA, directing the inhibition of the cGAS-Sting-IFNβ axis and inhibiting IFNβ secretion of macrophages.

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Fig. 1: FMD/fasting upregulates type I interferon responses in TAMs.
Fig. 2: FMD/fasting activates NRF1 and UPS in TAMs.
Fig. 3: Myeloid NRF1 knockout attenuates anti-tumour effects of FMD/fasting related to type I interferon responses.
Fig. 4: Fasting triggers NRF1-mediated ubiquitin/proteasome-dependent proteolysis of Trex1 in fasted TAMs.
Fig. 5: Trex1 binds to mtDNA in fasted mye-NFE2L1-/- TAMs.
Fig. 6: Trex1 blocking recovers activation of the cGAS-Sting-IFNβ axis in mye-NFE2L1-/- TAMs under FMD/fasting conditions.

Data availability

The RNA-seq generated from this study have been deposited in the National Genomics Data Center under the project accession PRJNA1234688. Any additional information required to reanalyse the data reported in this paper is available from the lead contact upon request.

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Acknowledgements

C.M. was supported by the Shanghai Clinical Research Center for Anaesthesiology (2023ZZ02001), the National Science and Technology Major Project of China (No2023YFA1800204), the Shanghai Municipal 2021 Science and Technology Innovation Action Plan (No.21JC1401400), the Shanghai Leading Talent (No. 2020-112), and the National Natural Science Foundation of China (NSFC, 82430068 and 82072213). T.H. was supported by funding from MOST (2021YFA0804700); NSFC (32070895, 92057105, 32225026); Foreign Experts Programs issued by Science & Technological Commission of Shanghai Municipality (STCSM, 22WZ2504000); and Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine at ShanghaiTech University and Shanghai Clinical Research and Trial Center, 201210, Shanghai, People’s Republic of China. Z.L. was supported by NSFC (82472212). W.J. was supported by funding from NSFC (32200715). Z.Z. was supported by funding from NSFC (82403441). We cordially thank Professor Tiffany Horng and Jiawei Yan from ShanghaiTech University for generating and providing mice with myeloid-specific knockdown of NRF1(NFE2L1).

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  1. These authors contributed equally: Zhe Luo, Tiffany Horng, Changhong Miao.

Authors and Affiliations

  1. Shanghai Institute of Infectious Disease and Biosecurity, Zhongshan Hospital, Fudan University, Shanghai, China

    Jiakun Li & Changhong Miao

  2. Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China

    Jiakun Li, Ziwen Zhong & Changhong Miao

  3. School of Life Sciences and Technology, ShanghaiTech University, Shanghai, China

    Wenjiao Jiang & Tiffany Horng

  4. Cardiac Intensive Care Center, Zhongshan Hospital, Fudan University, Shanghai, China

    Guowei Tu & Zhe Luo

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Contributions

J.L. designed the project, performed the experiments, analysed the data and wrote the manuscript. C.M. supervised the project, including the experimental design and funding support. T.H. provided mice with a myeloid-specific knock of NRF1(NFE2L1) and experimental equipment support. Z.L. provided suggestions for the revised manuscript and funding support. W.J. provided suggestions for manuscript revision and contributed important insights about proteolysis and related technical expertise, including CoIP and ChIP. G.T. and Z.Z. engaged the animal experiments and provided the FMD protocol.

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Correspondence to Zhe Luo, Tiffany Horng or Changhong Miao.

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Li, J., Jiang, W., Tu, G. et al. Fasting-mimicking diet induces IFNβ secretion in tumor-associated macrophages via NRF1-mediated ubiquitin-dependent proteolysis of Trex1. Br J Cancer (2026). https://doi.org/10.1038/s41416-025-03319-4

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