Dual compartment lipid carriers hijack exocytosis to empower natural killer cells against solid tumours.

Abstract

Solid tumours resist adoptive cell therapies through lactate driven immunosuppression, which depletes intracellular nicotinamide adenine dinucleotide, suppresses interferon gamma production in T cells, and reprogrammes macrophages. Here we show that a dual compartment lipid carrier system hijacks exocytosis for spatiotemporal metabolic reprogramming. Lipid nanoparticles deliver nicotinamide mononucleotide to restore intracellular nicotinamide adenine dinucleotide, while endoplasmic reticulum targeted carriers exploit the endoplasmic reticulum to Golgi pathway to achieve trafficking directed exocytic dichloroacetate export, enabling precise lactate depletion without systemic toxicity. This integrated approach rewires the metabolic landscape, extends natural killer cell persistence and reactivates cytolytic function. Endoplasmic reticulum engineered natural killer cells achieve potent tumour suppression through spatiotemporal metabolic reprogramming, a platform strategy that also extends to conventional T cell and macrophage therapies for enhanced therapeutic efficacy across adoptive cell systems. Our work establishes exocytosis co option as a strategy to empower cellular therapies and improve antitumour efficacy against lactate rich solid cancers.