Salt-inducible kinase 3 protects tumor cells from cytotoxic T-cell attack by promoting TNF-induced NF-κB activation

WHAT IS ALREADY KNOWN ON THIS TOPIC Tumor-intrinsic resistance to T cell (TC)-released cytokines, such as tumor necrosis factor (TNF)-α, has recently emerged as a major mechanism of tumor immune evasion. Yet, a deeper characterization of the genes that are responsible for this effect is needed. WHAT THIS STUDY ADDS Salt-inducible kinase 3 (SIK3) is a novel regulator of tumor-intrinsic resistance to cytotoxic TC attack. SIK3 confers tumor cell protection from TC-released TNF by sustaining the expression of pro-survival and anti-apoptotic genes under the control of nuclear factor kappa B (NF-κB). A TNF/SIK3/NF-κB-mediated gene signature correlated with significantly reduced patient survival in pancreatic cancer. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE AND/OR POLICY Pharmacological inhibition of SIK3 might be an effective strategy to sensitize cancer cells to TC-based immunotherapies by rewiring tumor cell responses to TC-secreted TNF.