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.