SUNGKYUNKWAN UNIVERSITY SCHOOL OF MEDICINE

Tumor necrosis factor superfamily (TNFSF) resistance contributes to the development and progression of tumors and the resistance to various cancer therapies. Tumor-intrinsic alterations involved in the adaption to the TNFSF response remain largely unknown. Here, we demonstrate that Protein kinase C substrate 80K-H (PRKCSH) abundance in lung cancers boosts oncogenic IGF1R activation, leading to TNFSF resistance. PRKCSH abundance was correlated with IGF1R upregulation in lung cancer tissues. Specifically, PRKCSH interacted with the IGF1R and extended its lifespan. The PRKCSH-IGF1R axis in tumor cells impaired caspase-8 activation, increased Mcl-1 expression, and inhibited caspase-9, leading to an imbalance between cell death and survival. PRKCSH deficiency augmented antitumor effects of natural killer (NK) cells, representative TNFSF effector cells, in a tumor xenograft IL-2Rg deficient NOD/SCID (NIG) mice model. Our data suggest that PRKCSH plays a critical role in TNFSF resistance and may be a potential target to improve NK cell-based cancer therapy.