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

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunotherapy

Background:

• Pyroptosis, a programmed cell death form, is a promising cancer immunotherapy strategy.
• Lonidamine typically induces apoptosis, not pyroptosis.

Purpose of the Study:

• To develop a self-assembling peptide-drug conjugate (LND-W) that induces pyroptosis in cancer cells.
• To evaluate the antitumor efficacy and immunogenic potential of LND-W, particularly when formulated as a hydrogel (Gel LND-W).

Main Methods:

• Creation of LND-W, a peptide-drug conjugate designed to self-assemble into nanofibers.
• Disruption of cancer cell membranes by LND-W nanofibers, triggering pyroptosis via ROS generation and GSDME activation.
• In vivo studies using 4T1 breast cancer models to assess tumor growth inhibition, metastasis, and immune response.

Main Results:

• LND-W successfully induced pyroptosis in cancer cells, characterized by IL-1β/IL-18 release and immunogenic cell death (ICD) marker exposure.
• Gel LND-W demonstrated enhanced tumor retention and significantly inhibited primary tumor growth and metastasis.
• Treatment with Gel LND-W activated both innate and adaptive immunity, with transcriptomic profiling showing increased pyroptosis-associated inflammatory pathways.

Conclusions:

• Peptide self-assembly is a viable strategy for inducing pyroptosis and enhancing cancer immunotherapy.
• LND-W and its hydrogel formulation represent a novel platform for developing effective immunogenic cancer therapies.