Survivin/BIRC5-derived peptide disrupts survivin dimerization and cell division and induces multifaceted anti-cancer effects

Survivin, a homodimeric protein overexpressed in virtually all cancers, is largely absent in non-proliferating adult tissues. It is a multifunctional regulator of cellular homeostasis that plays critical roles in proliferation, apoptosis, and immune regulation, which are central to cancer development and progression. Using a peptide array composed of sequences from SMAC/Diablo-interacting proteins, we identified a SMAC-binding sequence within survivin. Here, we report the characterization of a 24-amino-acid peptide spanning key survivin domains: the homodimer interface, microtubule, nuclear import, and chromosomal passenger complex binding sites. The peptide binds survivin and interferes with its dimerization, disrupting interactions with itself and partner proteins such as tubulin. When engineered as stabilized cell-penetrating peptides targeted to the cytosol, mitochondria, or nucleus, they effectively inhibited proliferation, disrupted the completion of mitosis, and induced apoptosis. In lung tumor models, the peptides reduced tumor cell proliferation and growth, while activating anti-tumor immune responses. They increased CD8⁺ T cell and NK cell infiltration and elevated PD-1/PD-L1 expression in the tumors. Additionally, they reduced the levels of survivin, SMAC, and tubulin, while increasing p53 expression in both <i>in vitro</i> and <i>in vivo</i> models. These findings highlight a novel strategy for targeting undruggable survivin using survivin-derived engineered peptides, offering promising therapeutic potential in cancer.