Stapled Wasp Venom-Derived Oncolytic Peptides with Side Chains Induce Rapid Membrane Lysis and Prolonged Immune Responses in Melanoma

Peptide
stapling chemistry represents an attractive strategy to
promote the clinical translation of protein epitope mimetics, but
its use has not been applied to natural cytotoxic peptides (NCPs)
to produce new oncolytic peptides. Based on a wasp venom peptide,
a series of stapled anoplin peptides (StAnos) were prepared. The optimized
stapled Ano-3/3s were shown to be protease-resistant and exerted superior
tumor cell-selective cytotoxicity by rapid membrane disruption. In
addition, Ano-3/3s induced tumor ablation in mice through the direct
oncolytic effect and subsequent stimulation of immunogenic cell death.
This synergistic oncolytic-immunotherapy effect is more remarkable
on melanoma than on triple-negative breast cancer in vivo. The efficacies exerted by Ano-3/3s on melanoma were further characterized
by CD8+ T cell infiltration, and the addition of anti-CD8 antibodies
diminished the long-term antitumor effects. In summary, these results
support stapled peptide chemistry as an advantageous method to enhance
the NCP potency for oncolytic therapy.