Immunobiological mechanisms of action of oncolytic peptides

Oncolytic peptides (OLPs) constitute an emerging class of immunotherapeutics that combine direct cancer cell lysis with immune activation. Indeed, OLPs induce rapid immunogenic cell death by disrupting intracellular membranes, which culminates with the abundant release of malignant cell contents including immunostimulatory danger-associated molecular patterns. This results in the engagement of innate immune sensors that potently activate dendritic cells, leading to the cross-priming of tumor-specific T lymphocytes that mediate systemic anticancer immunity. Through such a dual mechanism, OLPs can remodel the tumor microenvironment and overcome resistance to therapy as promoted by intratumoral heterogeneity, hence representing optimal combinatorial partners for immune checkpoint inhibitors. Some OLPs have also shown remarkable clinical efficacy. For instance, LTX-315 (studied as VP-315 in basal cell carcinoma (BCC)) has recently been shown to enable complete and durable responses in patients with BCC, and emerging evidence points to a significant activity of LTX-315 in immunologically cold tumors. Here, we summarize recent mechanistic, preclinical, and clinical advances in OLP development, underscoring their potential as a versatile and powerful modality of cancer immunotherapy.