Targeting the PSMD14-BCKDK pathway overcomes immune suppression and enhances CAR-NK infiltration in glioblastoma

Abstract Nutrient competition between tumor and immune cells is a hallmark of the glioblastoma (GBM) microenvironment, yet the mechanisms underlying amino acid metabolic reprogramming and immune evasion remain incompletely understood. Here, we demonstrate that GBM cells outcompete NK cells for branched-chain amino acid (BCAA), leading to BCAA depletion, suppression of NK and CD8 + T cell cytotoxicity, and immune escape. Mechanistically, we identify a positive feedback circuit involving PSMD14, BCKDK, and IGF2BP3 that stabilizes BCKDK post-translationally and promotes SLC7A5/SLC7A8-mediated BCAA uptake by GBM cells. PSMD14 directly interacts with and deubiquitinates BCKDK, antagonizing TRIM21-mediated proteasomal degradation. This metabolic remodeling disrupts NK cell signaling and function, as BCAA deprivation impairs PI3K/Akt and cGAS–STING pathways and disrupts mitochondrial integrity. Preclinical models reveal that pharmacologic inhibition of PSMD14 by O-phenanthroline (OPA) or PSMD14 knockdown restores immune cell infiltration, enhances CAR-NK cytotoxicity, and synergizes with immunotherapy to suppress GBM growth. Clinical analysis further establishes that elevated PSMD14 and BCKDK expression in GBM correlates with decreased CD8 + T and NK cell infiltration and poorer patient survival. These findings highlight the PSMD14–BCKDK axis as a central regulator of tumor metabolic adaptation and immune suppression, and support PSMD14 inhibition—alone or in combination with CAR-NK therapy—as a promising strategy for precision immunometabolic intervention in GBM.