Selective Pyroptosis in NF1-Deficient Cells through PKCδ Agonism

Abstract Pyroptosis, a lytic and immunogenic form of cell death, holds broad therapeutic potential, yet its selective induction in specific cell populations remains a fundamental challenge. Loss of the NF1 tumor suppressor, one of the most frequent events across pediatric and adult cancers, elevates RAS-GTP and drives tumorigenesis through hyperactivated RAS signaling. Here we demonstrate that protein kinase Cδ (PKCδ) agonism selectively triggers pyroptosis in NF1-deficient cells by exploiting their dependency on KRAS. PKCδ directly phosphorylates KRAS at S39 and S181, inducing KRAS-GDP accumulation and driving endoplasmic reticulum translocation. The dually phosphorylated KRAS-GDP interacts with caspase-8 and competitively displaces inhibitory BCL2, promoting caspase-8/caspase-3/gasdermin-E-mediated pyroptosis. This vulnerability is conserved across multiple NF1-deficient tumor types, and PKC agonism suppresses NF1-deficient neurofibroma and malignant peripheral nerve sheath tumor growth in vivo . These findings establish the inactive KRAS-GDP as a functionally active signaling molecule and PKCδ agonism as a selective therapeutic strategy for NF1-deficient cancers.