Targeting oral squamous cell carcinoma with venom peptides: mechanisms, selectivity and translational potential.

Venom-derived peptides represent a promising new class of biotherapeutics for oral squamous cell carcinoma (OSCC), offering intrinsic tumor selectivity and multimodal anticancer activity that address key limitations of current chemoradiotherapy. By exploiting the aberrant biophysical features of OSCC cell membranes-including externalized anionic phospholipids, enhanced membrane fluidity, and microvilli-rich surface topology-cationic, amphipathic venom peptides preferentially bind to and disrupt malignant cells, triggering mitochondrial depolarization, reactive oxygen species generation, cytochrome‑c release, and caspase‑dependent apoptosis, alongside autophagy-associated death and regulated necrosis. Beyond direct cytotoxicity, these peptides modulate critical oncogenic pathways by inducing cell‑cycle arrest via cyclin-dependent kinase inhibition, targeting overexpressed ion channels, and suppressing epithelial-mesenchymal transition, extracellular matrix degradation, migration, and VEGF‑driven angiogenesis, thereby attenuating invasion and metastatic dissemination in OSCC models. Concurrently, selected venom peptides remodel the immunosuppressive tumor microenvironment through macrophage repolarization, dendritic-cell activation, enhancement of cytotoxic T‑cell responses, and interference with immune checkpoint signaling, linking rapid tumor debulking with more durable immune control. Recent advances in nanotechnology-including liposomes, polymeric and gold nanoparticles, chitosan-based systems, silica nanocarriers, and extracellular vesicles-have substantially improved venom peptide stability, pharmacokinetics, tumor-specific accumulation, and stimulus-responsive release, while mitigating systemic toxicity and hypersensitivity risks in preclinical OSCC models. However, translation to routine clinical practice still requires rigorous resolution of immunogenicity, off‑target effects, manufacturing scalability, and standardized dosing through well-designed, OSCC-focused preclinical studies and early-phase trials. Overall, this review positions venom-derived peptides not merely as cytolytic toxins but as a modular platform for precision, multi-targeted intervention in oral cancer, integrating direct membrane lysis, signaling reprogramming, anti-angiogenic and anti-metastatic effects, and onco-immunomodulation into a unified therapeutic strategy.