Membranolytic peptide programs immunogenic cell death for cancer therapy

Area of Science:

• Biochemistry and Molecular Biology
• Immunology
• Oncology

Background:

• Innovative cell death strategies are crucial for advancing anti-tumor therapies.
• Immunogenic cell death (ICD) can stimulate anti-tumor immune responses.
• Current immunotherapies, like immune checkpoint blockade, can be enhanced by novel cell death induction methods.

Purpose of the Study:

• To design and implement a novel mode of immunogenic membranolytic cell death (mLCD) in tumor cells.
• To investigate the potential of this mLCD to enhance immune checkpoint blockade therapy.
• To develop a synthetic peptide capable of inducing this specific cell death mode.

Main Methods:

• Design and synthesis of an acid-responsive membranolytic peptide (aMP), aMP_C16-CA₅₀.
• Characterization of aMP-induced cell death, focusing on time-lagged membrane rupture.
• Evaluation of the peptide's effect on tumor cell immunogenicity, antigen presentation, and T cell activation.
• Assessment of the combination therapy's anti-tumor efficacy and systemic toxicity in preclinical models.

Main Results:

• The synthetic peptide aMP_C16-CA₅₀ induced a unique mode of mLCD characterized by time-lagged rupture from lysosomal to plasma membranes.
• This pH-responsive peptide activated an inflammatory transcriptional program, enhancing tumor cell antigen presentation and T cell activation.
• The spatiotemporal regulation of membrane rupture by the peptide critically enhanced tumor cell immunogenicity.
• Combination therapy with aMP_C16-CA₅₀ and immune checkpoint blockade showed enhanced anti-tumor efficacy.
• Systemic administration of the peptide was well tolerated in mice.

Conclusions:

• A novel synthetic pH-responsive membranolytic peptide was developed to induce a unique mode of immunogenic cell death in tumor cells.
• This approach, through spatiotemporal regulation of membrane rupture, robustly potentiates anti-tumor immune responses and enhances immune checkpoint blockade therapy.
• The designed peptide offers a promising strategy for improving cancer therapy by reprogramming tumor cell immunogenicity.