Targeting the DSTYK-ULK1 axis rewires TNFR1 signaling to overcome treatment resistance in lung cancer - PubMed
3 hours ago
- #immunotherapy
- #autophagy
- #lung cancer
- Immunotherapy has transformed NSCLC treatment, but acquired resistance remains a challenge.
- TNF-α from cytotoxic T cells promotes tumor cell death, while NF-κB supports survival.
- Autophagy inhibition enhances responses to immune checkpoint inhibitors (ICIs).
- DSTYK, a kinase amplified in NSCLC, suppresses TNF-α-mediated CD8+ T cell killing and drives ICI resistance via autophagy.
- DSTYK modulates TNFR1 signaling by phosphorylating ULK1, enabling ULK1-dependent phosphorylation of RIPK1.
- Loss of DSTYK disrupts ULK1 activation, promotes RIPK1 autophosphorylation, proapoptotic signaling, and impairs NF-κB-dependent survival.
- Targeting the DSTYK-ULK1-RIPK1 axis could sensitize DSTYK-amplified NSCLC to T cell-mediated killing.