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Nanoinducer-mediated mitochondria-selective degradation enhances T cell immunotherapy against multiple cancers

Nature Nanotechnology volume 20, pages 947–958 (2025)Cite this article

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Abstract

Cancer immunotherapy utilizing cytotoxic T lymphocytes has demonstrated significant promise in clinical applications, but cancer immunosuppressive mechanisms hamper further progress in T cell immunotherapy. Here we show a correlation between cancer cell mitochondrial content and their resistance to immunotherapy. Observing that cancer cells with higher mitochondrial content show increased resistance to CD8+ T cells, we developed mitochondrial nanoinducers designed to selectively target and degrade mitochondria within autophagosomes. The direct degradation of mitochondria not only enhances the recognition and activation of CD8+ T cells but also increases the susceptibility of cancer cells to CD8+ T cell-mediated cytotoxicity. We demonstrated the feasibility and efficacy of this strategy in multiple in vitro and in vivo tumour therapeutic models. This nanoinducer, designed to manipulate cellular mitochondrial degradation, holds promise as a versatile tool for enhancing adoptive T cell therapy, CAR-T cell therapy and tumour-vaccine-based immunotherapy.

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Fig. 1: CD8+ T cells preferentially target and eliminate the tumour cells with lower mitochondrial content.
Fig. 2: MitoNID-induced mitochondrial degradation through mitophagy.
Fig. 3: Treatment with mitoNIDs enhances the antitumour efficacy of adoptive CTLs.
Fig. 4: Treatment with mitoNIDs enhances the efficacy of CAR-T cell therapy against solid tumours.
Fig. 5: Treatment with mitoNIDs boosts the antitumour immune response of mRNA cancer vaccines.
Fig. 6: Mechanisms of mitoNIDs enhance CD8+ T cell cytotoxicity.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. There are no data from third-party or publicly available datasets. Raw data of non-targeted metabolomics analysis are deposited in MetaboLights and are accessible through accession number MTBLS12284. Due to the very large file sizes and volume of data, the remaining raw data are available from the corresponding author on reasonable request. Source data are available with this paper.

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Acknowledgements

This work was financially supported by the Fundamental Research Center Project (T2288102), the Research Grant (52361145850) of the National Natural Science Foundation of China and the Joint Project of Pinnacle Disciplinary Group, the Second Affiliated Hospital of Chongqing Medical. We thank the Core Facility of the Center of Biomedical Analysis, Tsinghua University, for assistance with confocal microscopy.

Author information

Author notes

  1. These authors contributed equally: Xueting Pan, Zhihang Wang, Mixiao Tan.

Authors and Affiliations

  1. CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China

    Xueting Pan, Zhihang Wang, Ziying Fu, Guangjun Nie & Hai Wang

  2. The Second Affiliated Hospital of Chongqing Medical University & Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing, China

    Mixiao Tan

  3. Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, China

    Ziying Fu

  4. Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, China

    Guangjun Nie & Hai Wang

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  1. Xueting Pan
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Contributions

H.W. conceived the project. H.W., X.P., G.N., M.T. and Z.W. analysed the data and wrote the manuscript. Z.W. and X.P. conducted all the experiments with help from M.T. and Z.F. All authors approved the manuscript.

Corresponding author

Correspondence to Hai Wang.

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The authors declare no competing interests.

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Nature Nanotechnology thanks Jianliang Shen and Luca Simula for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Schematic representation of mitoNID-mediated mitochondria degradation for enhanced CD8+ T cell therapy.

Treatment with mitoNIDs facilitates mitophagy by promoting the proximity between mitochondria and autophagy-related protein LC3, consequently stimulating mitochondrial degradation within tumor cells. This process elevates the level of the metabolite LPI, triggering the activation of the GPR55-ErK signaling pathway, thereby fostering the proliferation of CD8+ T cells. Furthermore, mitochondrial degradation leads to the upregulation of MHC-I expression and the downregulation of BCL-XL expression in tumor cells, consequently enhancing tumor cell recognition and sensitivity by CD8+ T cells. In vivo immunotherapy strategies, including adoptive T-cell therapy, CAR T-cell therapy, and mRNA cancer vaccines, were validated for the enhanced therapeutic outcomes through the co-administration of mitoNIDs.

Extended Data Fig. 2 MitoNIDs boost the killing ability of CD8+ T cells against tumor cells.

a, Schematic diagram illustrating the experimental process of mitoNIDs enhancing CD8+ T cell toxicity. b, Images of B16-OVA tumor cells after treatment with various E:T ratios of OT-1 CD8+ T cells with or without mitoNIDs. Scale bar, 50 μm. c, LDH release in the culture supernatant. d, The degree of apoptosis of B16-OVA tumor cells detected by flow cytometry. e, Cell viability of OT-1 CD8+ T cell-treated B16-OVA tumor cells. f, Immunoblots showing cleaved caspase-3 in B16-OVA tumor cells after treatment with mitoNIDs and OT-1 CD8+ T cells. g, Images of A549 tumor cells after treatment with EGFR-CAR-T cells with or without mitoNIDs. Scale bar, 50 μm. h, The degree of apoptosis of A549 tumor cells detected by flow cytometry. i, Cell viability of EGFR-CAR-T cell-treated A549 tumor cells. j, Schematic diagram illustrating the experimental process of mitoNIDs overcoming the tolerance of tumor cells to CD8+ T cells. k, Images of B16-OVA tumor cells after treatment with OT-1 CD8+ T cells with or without mitoNIDs. Scale bar, 50 μm. l, LDH release in the culture supernatant. m, The degree of apoptosis of B16-OVA cells detected by flow cytometry. n, Cell viability of B16-OVA tumor cells. o, Immunoblots showing cleaved caspase-3 in B16-OVA cells after treatment with mitoNIDs and OT-1 CD8+ T cells. p, Microscopic images of A549 tumor cells after treatment with EGFR-CAR-T cells with or without mitoNIDs. Scale bar, 50 μm. q, The degree of apoptosis of A549 tumor cells detected by flow cytometry. r, Cell viability of EGFR-CAR-T cell-treated A549 tumor cells. All data are shown as the mean ± s.d. (n = 3 biologically independent cell samples). Two-way ANOVA with Šídák’s multiple comparison was used to calculate statistical differences in c, d, e, h, i, l, m, n, q and r.

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Supplementary Figs. 1–57, Tables 1, experimental procedures, unprocessed western blots and references.

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Source Data Extended Data Fig. 2

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Pan, X., Wang, Z., Tan, M. et al. Nanoinducer-mediated mitochondria-selective degradation enhances T cell immunotherapy against multiple cancers. Nat. Nanotechnol. 20, 947–958 (2025). https://doi.org/10.1038/s41565-025-01909-0

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