Targeting ribosomes reprograms the tumour microenvironment and augments cancer immunotherapy
Creators
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1.
Wuxi Fourth People's Hospital
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2.
Jiangnan University
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3.
Nanjing Medical University
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4.
Shenzhen Institutes of Advanced Technology
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5.
Sun Yat-sen University
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6.
California Institute of Technology
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7.
Macau University of Science and Technology
Abstract
Background
Hyperactive ribosome biogenesis is a hallmark of tumours. Current ribosome-related studies are concentrated on cancer cells. Ribosomes can regulate both tumour and non-cancer cells within the tumour microenvironment, yet the immunomodulatory effects of cellular ribosome biogenesis blockade remain inadequately understood.
Methods
We performed ribosome-targeting therapy utilizing CX-5461, an effective and acknowledged selective inhibitor of ribosome biogenesis, in immunocompetent in vivo models and submitted for single-cell RNA sequencing (scRNA-seq). Additional large-scale human scRNA-seq data, in-house clinical samples and assays were used.
Results
Ribosome inhibition elevated lymphoid cell cytotoxic granule secretion and macrophage pro-inflammation reprogramming. We uncovered unique immune cell subpopulations that are sensitive to ribosome biogenesis blockade and are associated with adverse clinical outcomes. Impressively, these cells regress during responsive immune checkpoint blockade (ICB) treatment, revealing that they are essential for immunotherapy efficacy. Moreover, targeting ribosomes induces immune checkpoint expression (such as Lag3) and significantly sensitizes tumours to anti-Lag3 immunotherapy, eliciting potent tumour regression and deeper anti-tumour immune responses.
Conclusions
These findings unravel previously unrecognized roles of cellular ribosome biogenesis in sustaining immunosuppressive non-cancer cells. Our work unveils that ribosome biogenesis blockade could reinstate immunosurveillance and provide novel strategies to enhance the ICB efficacy in patients with poor immunogenicity.
Copyright and License
© 2025, The Author(s). This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Acknowledgement
We thank developers of previous datasets, algorithms and R packages used in this study. We would like to thank the Jiangnan University Medical Center for providing clinical samples. We thank the platforms of Medical Research Center (Wuxi School of Medicine, Jiangnan University). We thank Prof. Xiaodi Yang (Bengbu Medical University) and Dr. Shengbai Sun (Zhejiang University) for kindly and useful support.
Funding
This work was supported by grants from the National Natural Science Foundation of China (T2250710184 to YM Zhang; 82472671 to KS Cui; 82303115 to ZC Gong); The Jiangsu Provincial Key Medical Discipline (ZDXK202227 to XJ Lu); Shenzhen Science and Technology Plan Platform and Carrier Special Project (ZDSYS20220303153551001 to YM Zhang); Wuxi Taihu Talent Program (WX0302B010507200065 to XJ Lu).
Contributions
K.C. initiated the entire study. X.L., YM.Z. and K.C. supervised this project and mentored the participants. K.C., B.L., L.G., Z.G., Q.Z., YZ.Z. and YM.Z. designed therapy experiments and related assays; L.G. performed the therapy experiments and related assays; L.G. and Q.W. performed functional experiments and related assays of the revised manuscript. K.C., B.L., Q.W., R.S., C.W. and X.L. designed the in-house clinical validation; Q.W., R.S., B.L. and K.C. performed in-house clinical samples collective and information maintenance; H.T. constructed FFPE tissue slides; B.L. performed the multicolor-immunostaining assay. K.C. designed and performed the in-silico analysis and visualization; B.L. and Q.L. provided support for these. All authors revised the manuscript and discussed results. All authors agreed to submit this manuscript, read and approved the final draft and take full responsibility of its content.
Ethics
This work was approved by the Medical Ethic Committee of Jiangnan University Medical Center (Permit No. 2023-Y-70), all patients provided written informed consent. All animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee of Shenzhen Institutes of Advanced Technology, Chinese Academy of Science (Permit No. SIAT-IACUC-230904-HCS-ZYM-A2317). All methods were performed in accordance with the relevant guidelines and regulations.
Supplemental Material
Supplementary information: 41416_2025_3109_MOESM1_ESM.pdf
Data Availability
Available of public datasets are described in the ‘Public data and resources’ section. All other data supporting the findings of this study are available from the corresponding author on reasonable request.
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Additional details
Related works
- Describes
- Journal Article: https://rdcu.be/ewSUg (ReadCube)
Funding
- National Natural Science Foundation of China
- T2250710184
- National Natural Science Foundation of China
- 82472671
- National Natural Science Foundation of China
- 82303115