To our knowledge, this is the first report that SERPINB3 protects cancer cells against radiation-induced necrosis, and does so via inhibition of the lysosomal cysteine protease cathepsin L. Moreover, we present evidence that ionizing radiation induces a lysosome-mediated cell death pathway in cancer cells, particularly when a protective factor is eliminated, suggesting a potential vulnerability for targeting radioresistant cancers. The gene discussed is SERPINB3; the disease is cancer.