Abstract
The tumour microenvironment (TME) causes mitochondrial dysfunction in resident dendritic cells (DCs), resulting in inadequate antigen presentation and weak T cell priming. Herein, we identify hypoxia as a key factor for causing pathological mitochondrial fission in tumour-associated DCs, and develop a plant vesicle-DC chimera to relieve hypoxia-induced mitochondrial dysfunction for enhancing cancer immunotherapy. The biohybrid chimera is fabricated by loading algae-derived nanovesicles (ANVs) with genetically engineered CCR2 overexpressing-DCs. The CCR2-DC-ANVs target tumour by leveraging the C-C motif chemokine ligand 2 (CCL2) in tumours. Upon light exposure, the ANVs produce oxygen and NADPH to resolve hypoxic and oxidative stress, which reverse pathological mitochondrial fission in DCs. Mitochondrial network restoration alleviates endoplasmic reticulum stress, reduces lipid droplet accumulation, and initiates metabolic reprogramming to enhance antigen presentation and T cell priming of CCR2-DC-ANVs in the TME. The biohybrid chimera enhances therapeutic efficiency in humanized mouse models of breast cancer in female mice without requiring external tumour antigens. This approach highlights a cross-species chimera for next-generation DC therapy, and provides the basis for a nanobiotechnology platform to facilitate organelle medicine by combining photosynthesis with immunotherapy.
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Acknowledgements
The authors are grateful to the staff members of the Integrated Laser Microscopy System and Mass Spectrometry System at the National Facility for Protein Science in Shanghai (NFPS), Shanghai Advanced Research Institute, Chinese Academy of Sciences, China for the instrument support (Fortessa flow cytometer) and technical assistance during data collection. We are grateful to Y. Wang and F. Liu from NFPS for FACS and confocal microscopy training. We thank F. Hu from Biotech Pack Scientific Co., Ltd. (Beijing, China) for analyzing immunopeptidomics data.
Funding
Financial support from Strategic Priority Research Program of the Chinese Academy of Grant (XDC0290302, XDB1020000 to Y.L.), National Natural Science Foundation of China (32130058, 32561160090 to Y.L.), the Science and Technology Development Fund of Macau (FDCT/0150/2025/AFJ to Q.Z.), National Key R&D Program of China (2022YFC3401404 to Y.L.), Science and Technology Commission of Shanghai Municipality (24J22800600 to Y.L.) and Shandong Laboratory Program (SYS202205 to Y.L.) and are gratefully acknowledged.
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Yi, W., Qian, X., Yan, W. et al. A plant vesicle-dendritic cell chimera for enhancing cancer immunotherapy. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73788-5
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DOI: https://doi.org/10.1038/s41467-026-73788-5
