High-Entropy-Engineered Nanoinducer for Spatiotemporally Programmed PANoptosis and NIR-Amplified Cancer Immunotherapy.

Abstract

PANoptosis has emerged as a compelling strategy to potentiate antitumor immune responses. However, achieving specific PANoptotic cancer-cell death while sparing normal tissues remains a central challenge, as current strategies are constrained by inadequate spatiotemporal controllability and insufficient generation of key effector species, particularly reactive oxygen species (ROS). In this study, we report a class of PANoptosis nanoinducer constructed from atomically dispersed high-entropy metal sites, enabling spatiotemporally controlled near-infrared (NIR)-amplified cancer immunotherapy. The unique high-entropy metal-site configuration of the resulting nanozymes (HENA@PEG) boosts catalytic efficiency through atomic-level synergism, while enabling precise, pH-gated control over ROS generation via catalytic activation. In addition, nanozyme-mediated photothermal therapy (PTT) not only induces direct tumor ablation but also supplies exogenous thermal energy to accelerate the catalytic reactions. The co-programmed integration of endogenous and exogenous activations confers tumor-site-adaptive biocatalysis, thereby enabling precise spatiotemporal induction of PANoptosis. Both in vitro and in vivo investigations reveal that the resulting nanoinducer effectively promotes dendritic cell maturation and cytotoxic T-cell activation, ultimately amplifying antitumor immune responses and markedly suppressing 4T1 tumor progression. Overall, this work establishes a high-entropy-engineered nanoinducer that overcomes the limitations of nonspecific PANoptosis and immune evasion, representing a promising avenue toward more efficient and precisely targeted cancer immunotherapy.