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.