Advancing Precision: A Controllable Self-Synergistic Nanoplatform Initiating Pyroptosis-Based Immunogenic Cell Death Cascade for Targeted Tumor Therapy

Abstract

Heterogeneity of the tumor microenvironment (TME) is primarily responsible for ineffective tumor treatment and uncontrolled tumor progression. Pyroptosis-based immunogenic cell death (ICD) therapy is an ideal strategy to overcome TME heterogeneity and obtain a satisfactory antitumor effect. However, the efficiency of current pyroptosis therapeutics, which mainly depends on a single endogenous or exogenous stimulus, is limited by the intrinsic pathological features of malignant cells. Thus, it is necessary to develop a synergistic strategy with a high tumor specificity and modulability. Herein, a synergistic nanoplatform is constructed by combining a neutrophil camouflaging shell and a selfsynergistic reactive oxygen species (ROS) supplier-loaded polymer. The covered neutrophil membranes endow the nanoplatform with stealthy properties and facilitate sufficient tumor accumulation. Under laser irradiation, the photosensitizer (indocyanine green) exogenously triggers ROS generation and converts the laser irradiation into heat to upregulate NAD(P)H:quinone oxidoreductase 1, which further catalyzes β-Lapachone to self-produce sufficient endogenous ROS, resulting in amplified ICD outcomes. The results confirm that the continuously amplified ROS production not only eliminates the primary tumor but also concurrently enhances gasdermin E-mediated pyroptosis, initiates an ICD cascade, re-educates the heterogeneous TME, and promotes a systemic immune response to suppress distant tumors. Overall, this self-synergistic nanoplatform provides an efficient and durable method for redesigning the immune system for targeted tumor inhibition.

Dual-Responsive Epigenetic Inhibitor Nanoprodrug Combined with Oncolytic Virus Synergistically Boost Cancer Immunotherapy by Igniting Gasdermin E-Mediated Pyroptosis

“…Previous studies have indicated that OVs can trigger tumor cell pyroptosis. , Pyroptosis is a form of inflammatory cell death characterized by cell swelling, membrane rupture, and the release of immunogenic substances. − Pyroptosis is thought to be gasdermin-mediated programmed cell death. Notably, gasdermin E (GSDME)-mediated pyroptosis plays a critical role in the context of antitumor immunity . It has been shown that the expression level of GSDME is a determinant of the mode of transformed cell death and that spontaneous pyroptosis occurs only in tumors with high GSDME expression .…”