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.