Targeting the PSMD14-BCKDK pathway overcomes immune suppression and enhances CAR-NK infiltration in glioblastoma - PubMed
4 hours ago
- #immune suppression
- #glioblastoma
- #CAR-NK therapy
- Nutrient competition between tumor and immune cells is a key feature of the glioblastoma (GBM) microenvironment.
- GBM cells outcompete NK cells for branched-chain amino acids (BCAAs), leading to immune suppression and escape.
- A feedback circuit involving PSMD14, BCKDK, and IGF2BP3 stabilizes BCKDK and promotes BCAA uptake by GBM cells.
- PSMD14 deubiquitinates BCKDK, preventing its degradation and disrupting NK cell signaling and function.
- BCAA deprivation impairs PI3K/Akt and cGAS-STING pathways and mitochondrial integrity in NK cells.
- Pharmacologic inhibition of PSMD14 or its knockdown restores immune cell infiltration and enhances CAR-NK cytotoxicity.
- Elevated PSMD14 and BCKDK in GBM correlate with reduced immune cell infiltration and poorer patient survival.
- Targeting the PSMD14-BCKDK axis presents a promising strategy for GBM treatment, especially in combination with CAR-NK therapy.