Self-Assembling Peptides Alter Cell Death Pathway for Pyroptosis-Enhanced Immune Activation

Pyroptosis, a pro-inflammatory form of programmed cell death, represents a promising strategy for cancer immunotherapy by eliciting robust antitumor immunity. Herein, we developed Lonidamine-WEWTWY (LND-W), a self-assembling peptide-drug conjugate that reprograms the cell death mechanism of Lonidamine from apoptosis to pyroptosis. The LND-W conjugate spontaneously forms stable nanofibers that selectively disrupt cancer cell membranes, triggering pyroptosis through membrane damage, reactive oxygen species (ROS) generation, and gasdermin E (GSDME) activation. In 4T1 breast cancer models, LND-W induced characteristic pyroptotic features, including Interleukin-1beta (IL-1β)/Interleukin-18 (IL-18) release and immunogenic cell death (ICD) marker exposure. When formulated as an injectable hydrogel (Gel LND-W), the system demonstrated enhanced tumor retention and superior antitumor efficacy, significantly inhibiting primary tumor growth and metastasis while activating both innate and adaptive immunity. Transcriptomic profiling revealed upregulation of pyroptosis-associated inflammatory pathways in treated tumors. This work establishes peptide self-assembly as a powerful approach to induce pyroptosis and advances a novel platform for immunogenic cancer therapy.