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

Despite the clinical promise of cytokine-induced memory-like (CIML) 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 (SSA) 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.