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Inhaled nanosilica orchestrates a pulmonary macrophage-NK cell axis for memory-like NK programming toward synergistic cancer immunotherapy.

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Title: Inhaled nanosilica orchestrates a pulmonary macrophage-NK cell axis for memory-like NK programming toward synergistic cancer immunotherapy.
Authors: Yuan F; Laboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Laboratory of Immunology and Nanomedicine, and China-Italy Joint Laboratory of Pharmacobiotechnology for Medical Immunomodulation, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China., Li Q; Laboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Laboratory of Immunology and Nanomedicine, and China-Italy Joint Laboratory of Pharmacobiotechnology for Medical Immunomodulation, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China., Liu Y; Laboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Laboratory of Immunology and Nanomedicine, and China-Italy Joint Laboratory of Pharmacobiotechnology for Medical Immunomodulation, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China., Liu F; Laboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Laboratory of Immunology and Nanomedicine, and China-Italy Joint Laboratory of Pharmacobiotechnology for Medical Immunomodulation, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China., Luo W; Laboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Laboratory of Immunology and Nanomedicine, and China-Italy Joint Laboratory of Pharmacobiotechnology for Medical Immunomodulation, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China., Song Q; Laboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Laboratory of Immunology and Nanomedicine, and China-Italy Joint Laboratory of Pharmacobiotechnology for Medical Immunomodulation, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China., Zeng Y; Laboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Laboratory of Immunology and Nanomedicine, and China-Italy Joint Laboratory of Pharmacobiotechnology for Medical Immunomodulation, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China., Bi J; State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China., Zhang G; Laboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Laboratory of Immunology and Nanomedicine, and China-Italy Joint Laboratory of Pharmacobiotechnology for Medical Immunomodulation, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China., Li Y; Laboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Laboratory of Immunology and Nanomedicine, and China-Italy Joint Laboratory of Pharmacobiotechnology for Medical Immunomodulation, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; State Key Laboratory of Biomedical Imaging Science and System, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. Electronic address: yang.li@siat.ac.cn.
Source: Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2026 Oct 07; Vol. 34 (10), pp. 5831-5857. Date of Electronic Publication: 2026 Sep 02.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Cell Press Country of Publication: United States NLM ID: 100890581 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1525-0024 (Electronic) Linking ISSN: 15250016 NLM ISO Abbreviation: Mol Ther Subsets: MEDLINE
Imprint Name(s): Publication: 2017- : Cambridge, MA : Cell Press
Original Publication: San Diego, CA : Academic Press, 2000-
MeSH Terms: Killer Cells, Natural*/immunology , Killer Cells, Natural*/drug effects , Killer Cells, Natural*/metabolism , Silicon Dioxide*/administration & dosage , Silicon Dioxide*/chemistry , Macrophages, Alveolar*/immunology , Macrophages, Alveolar*/drug effects , Macrophages, Alveolar*/metabolism , Immunotherapy*/methods , Immunologic Memory*/drug effects , Nanoparticles*/administration & dosage , Nanoparticles*/chemistry, Animals ; Mice ; Humans ; Cell Line, Tumor ; Disease Models, Animal ; Female ; Administration, Inhalation
Abstract: Despite the clinical promise of cytokine-induced memory-like (CIML) natural killer (NK) cells, widespread translation is hindered by the high cost and complexity of ex vivo manufacturing. Here, we show that the lung functions as an in vivo programming niche that generates functional CIML NK cells for systemic cancer immunotherapy and immunoprevention. By decoupling immunostimulation from silicosis, we identify an obligate alveolar macrophage (AM)-NK cell axis. Upon engulfing biodegradable amorphous nanosilica (nSiO2), AMs release a transient IL-12/15/18 triad that reprograms circulating NK cells into memory-like effectors. The resulting NK cells meet all three canonical CIML criteria: proliferative expansion, transition to an armed resting state, and enhanced IFN-γ recall upon tumor rechallenge, with specific surface area serving as a key physical determinant of programming potency. In mouse models, a brief prophylactic pulmonary nSiO2 regimen (120 μg/dose, 4 doses) establishes durable (≥60 days) protective immunity, suppresses melanoma growth, prevents postsurgical recurrence, and synergizes with anti-PD-1 therapy in an NK-dependent manner. Crucially, this therapeutic regimen does not induce pulmonary fibrosis; the amorphous nSiO2 is completely biodegraded and cleared within 90 days, with no detectable systemic toxicity. Our study establishes a cell-free framework for in vivo NK cell programming, informing next-generation cancer immunotherapies.
(Copyright © 2026 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of interests The authors declare no competing interests.
Contributed Indexing: Keywords: In vivo cellular programming; In vivo immune programming; alveolar macrophages; cancer immunoprevention; cytokine-induced memory-like NK cells; nanosilica
Substance Nomenclature: 7631-86-9 (Silicon Dioxide)
Entry Date(s): Date Created: 20260903 Date Completed: 20261007 Latest Revision: 20261020
Update Code: 20261020
PubMed Central ID: PMC13673553
DOI: 10.1016/j.ymthe.2026.08.046
PMID: 42687379
Database: MEDLINE
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