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Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells

Abstract

Cancer progresses by evading the immune system. Elucidating diverse immune evasion strategies is a critical step in the search for next-generation immunotherapies for cancer. Here we report that cancer cells can hijack the mitochondria from immune cells via physical nanotubes. Mitochondria are essential for metabolism and activation of immune cells. By using field-emission scanning electron microscopy, fluorophore-tagged mitochondrial transfer tracing and metabolic quantification, we demonstrate that the nanotube-mediated transfer of mitochondria from immune cells to cancer cells metabolically empowers the cancer cells and depletes the immune cells. Inhibiting the nanotube assembly machinery significantly reduced mitochondrial transfer and prevented the depletion of immune cells. Combining a farnesyltransferase and geranylgeranyltransferase 1 inhibitor, namely, L-778123, which partially inhibited nanotube formation and mitochondrial transfer, with a programmed cell death protein 1 immune checkpoint inhibitor improved the antitumour outcomes in an aggressive immunocompetent breast cancer model. Nanotube-mediated mitochondrial hijacking can emerge as a novel target for developing next-generation immunotherapy agents for cancer.

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Fig. 1: Cancer cells and effector immune cells connect via physical nanotubes.
Fig. 2: Nanotubes mediate organelle transfer between immune cells and cancer cells.
Fig. 3: Metabolic effect of mitochondrial hijacking.
Fig. 4: Mechanism underlying nanotube formation and mitochondrial transfer.
Fig. 5: Targeting nanotube-mediated mitochondrial hijacking augments antitumour immune response in vivo.

Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

This work is supported by grants from the National Institute of Health (NIH AR073135_HLJ, CA236702_SS_HLJ, CA214411_SS and CA229772_SS_Co-I), American Lung Association Discovery Grant (LCD-618834_SS) and Department of Defense (DoD PC180355_HLJ and CA201065_HLJ). This work was performed in part at the Center for Nanoscale Systems (CNS), Harvard University, a member of the National Nanotechnology Coordinated Infrastructure Network (NNCI), supported by the National Science Foundation. We thank M. Haigis and A. Goldman for help with the PhAM mouse studies. K.K. is a Gilead Sciences Fellow of the Life Sciences Research Foundation.

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T.S. conceived the project, designed and executed the experiments, analysed the data, prepared the figures, and contributed to writing the manuscript. C.D. and R.J. helped in designing and executing the in vitro experiments. S.K. and J.M. helped in designing and executing the in vivo studies and analysed results. A.K. performed the genotyping experiment, analysed results and helped write the manuscript. K.K. helped with the Dendra2 mice and Seahorse studies. P.K.M. and A.B. helped with human tumour explant studies and contributed to the manuscript writing. H.L.J. and S.S. conceptualized and supervised the project, and guided the experimental design, data analysis and manuscript writing.

Corresponding authors

Correspondence to Hae Lin Jang or Shiladitya Sengupta.

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Competing interests

S.S. is a co-founder and owns equity in Vyome Therapeutics, Akamara Therapeutics and Invictus Oncology, and receives fees from Famygen and Advamedica. H.L.J. is a founder and owns equity in Curer. A.B. is involved in the following consulting/advisory boards: Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Taiho, Sanofi, Daiichi Pharma/AstraZeneca, Puma, Biothernostics, Phillips, Eli Lilly and Foundation Medicine; A.B. is also contracted via research/grant to the following institutions: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, Daiichi Pharma/AstraZeneca and Natera. T.S., C.D., R.J., S.K., A.K., K.K., J.M. and P.K.M. declare no competing interests.

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Supplementary Figs. 1–29 and Table 1.

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Saha, T., Dash, C., Jayabalan, R. et al. Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells. Nat. Nanotechnol. (2021). https://doi.org/10.1038/s41565-021-01000-4

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