Malignant pleural effusion (MPE), persistently generated by thorax tumor cells at the advanced stage, remains a major challenge for cancer therapy. Herein, we develop an ultra-sensitive piezoelectric nano-system by doping ytterbium in metal-organic framework (O3P@LPYU), which can be triggered by physiological intrapleural pressure during breath. Under the gently alterative pressure, the piezoelectric nanoparticles with notable peroxidase-like activity effectively produce a burst of reactive oxygen species and induce immunogenic cell death by catalysis of carried ozone as well as peroxide in interstitial fluid. A clear and sustained biodistribution is observed in thorax effusion and tumors upon intrapleural administration of particle. Remarkably, due to the abundant substrates in oxygen-rich environment of pleural cavity, O3P@LPYU particle provides a potent reduction of MPE volume and durable inhibition of tumor growth in thorax. Our work not only develops a bio-responsive piezoelectric nano-system, but also provides a strategy for persistent suppression of MPE in clinics.© 2025. The Author(s).