Light-responsive nanocarrier-based drug delivery systems (NDDSs), due to their unique advantages such as safety, minimal cross-reaction, and spatiotemporal precision, have received wide attention. Notably, second near-infrared (NIR-II) light, which has a high penetration depth for manipulating NDDSs to release drugs, is in high demand. Herein, polyethylene glycol (PEG)-modified hollow Cu x S nanoparticles (NPs) are developed as an all-in-one NIR-II light-responsive NDDS for synergistic chemo-photothermal therapy. First, Cu x S-PEG NPs were prepared under mild conditions by using Cu 2 O NPs as sacrificial templates. The morphology, photothermal effect, drug loading/releasing abilities, and synergistic chemo-photothermal therapy of Cu x S-PEG NPs have been investigated. The Cu x S-PEG NPs with hollow structures showed a high drug loading capacity (∼255 μg Dox per mg of Cu x S NPs) and stimuli-responsive drug release triggered by NIR-II laser irradiation. The synergistic chemo-photothermal therapy based on the Dox/Cu x S-PEG NPs showed 98.5% tumor elimination. Our study emphasizes the great potential of Cu x S-PEG NPs as an all-in-one NIR-II light-responsive NDDS for applications in biomedicine.