Developing redox nanozymes able to disrupt cellular homeostasis and promoting immunotherapy offers great potentials to develop highly efficient cancer therapy, but remains challenging. Herein, we initially proposed a high entropy-based layered double hydroxide (LDH) nanosheets (denoted as HE-NS) regulation strategy to achieve high yields of reactive oxygen species (ROS), breaking relatively vulnerable homeostasis, remodeling the tumor microenvironment (TME), further trigger cell pyroptosis. Specifically, compared with low entropy and medium entropy LDH, this unique HE-NS exhibits better multienzyme catalytic activity, which can be further enhanced under ultrasound (US) irradiation. Density functional theory (DFT) calculations confirm that this superior performance can be attributed to the multi-element environment in HE-NS, which optimally modulates the electronic structure of the Fe active site. This modulation yields an intermediate hydrogen peroxide (H 2 O 2 ) adsorption strength, thereby significantly reducing the energy barrier for superior peroxidase (POD)-like activity. The HE-NS can significantly induce pyroptosis, which further eliciting an adaptive immune response, leading to immunogenic cell death (ICD). The reprogramming of the immunosuppressive TME by HE-NS has been confirmed by both in vitro and in vivo studies. This study proposed a new strategy of ultrasound-enhanced pyroptosis-mediated immunotherapy, which effectively enhanced the therapeutic effect.
Yang et al. (2026) studied this question.