Abstract
Recent clinical studies highlight the effectiveness of combining cytotoxic agents with immunotherapies, emphasizing the need for next-generation treatments that integrate both therapeutic approaches. Here, we use 30 cancer cell lines, 15 tumor models, and 45 patient samples to develop N17350, a therapeutic elastase that targets the "neutrophil elastase pathway" to induce tumor regression and stimulate anti-tumor immunity. N17350 leverages linker histone H1.0 and H1.2, proteins elevated in many cancers, to trigger immunogenic cancer cell death while preserving immune cells. Intra-tumoral N17350 administration induces rapid, genotype-independent tumor regression, triggering CD8+ T cell activation to promote durable responses and enable checkpoint inhibitor efficacy in refractory models. N17350 maintains potency with repeated dosing and across diverse treatment histories, including resistance to chemotherapies and checkpoint inhibitors. These findings support the advancement of N17350 to first-in-human clinical trials as a cytotoxic agent designed to stimulate anti-tumor immunity by selectively killing cancer cells.