Abstract
Regulating intracellular phosphorus may affect multiple biosynthetic processes and modulate cancer cell progression. Here we show that exogenous PEGylated black phosphorus nanosheets (BPP) are metabolized into phosphate in tumor cells, where they boost mitochondrial oxidative phosphorylation. This results in the modulation of several signalling pathways, with the attenuation of prosurvival gene expression and reduction in PD-L1 protein expression in melanoma cells, leading to impaired cancer progression. We also reveal that BPP promote the activation of immune regulation, confirmed by the increased proinflammatory cytokine content in serum, high expression of tumour-infiltrating lymphocyte CD8+ T cells and lower expression of CD4+ regulatory T cells in tumour and lymph nodes. In the spleen, BPP mediate a significant increase in the concentration of effector memory CD8+ T cells, inducing a ‘positive regulation’ of the immune microenvironment. The introduction of a PD-1/PD-L1 inhibitor further enhances the immunopotentiation effect. These findings may define BPP as a dual-function tumour chemotherapeutic and immunopotentiator.
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Data availability
The data that support the findings of this study are available within the Article and its Supplementary Information. The raw data of the transcriptome sequencing have been deposited in The National Center for Biotechnology Information Sequence Read Archive (http://www.ncbi.nlm.nih.gov/sra/) with the accession number PRJNA1287216 for the tumour and PRJNA1286125 for the spleen. The mass spectrometry proteomics data have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD066855. Source data are provided with this paper.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (grant numbers 32422044, 32271419 (Y.S.) and 32471416, 51973136 (Y.F.)) and Varnotech-Sichuan University Joint Laboratory on ‘Development and Application of Novel Immunologic Adjuvant’ (grant number 24H0599, Y.S.). We thank Varnotech Biopharm Ltd and its directors H. Wang and G. Liu for their suggestions in the preclinical evaluation of BPP.
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Y.Y. and M.Z. contributed to the execution and analysis of all the experiments. J. Li contributed to the execution and analysis of supplementary experiments. R.X. contributed to the synthesis and preparation of hydrogels and animal studies. J. Liang and Q.J. contributed to the in vitro cell proliferation and tissue processing. X.P., A.T., L.M. and Y.L. contributed to the data analysis and article modification. X.Z. provided research guidance. Y.F. and Y.S. conceived the project and contributed to the study design and result analysis. Y.Y., M.Z., Y.F. and Y.S. prepared the manuscript, with inputs from all authors.
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In vitro cytotoxicity test—direct-contact test.
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Test for systemic toxicity: acute systemic toxicity test (direct application—subcutaneous route).
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Yang, Y., Zhao, M., Li, J. et al. Black phosphorus nanosheets boost mitochondrial oxidative phosphorylation improving immunotherapy outcomes. Nat. Nanotechnol. 20, 1843–1855 (2025). https://doi.org/10.1038/s41565-025-02022-y
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DOI: https://doi.org/10.1038/s41565-025-02022-y
