Targeting SLC6A14-mediated nutrient competition reverses an immunosuppressive metabolic niche in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) exhibits an immunosuppressive and nutrient-deficient tumor microenvironment (TME), where solute carrier (SLC) transporters are critical in metabolic reprogramming and intercellular communication. However, the precise mechanisms by which specific SLCs contribute to therapeutic resistance through the TME remain unclear. We integrated transcriptomic data from clinical cohorts with computational analysis and expression validation to identify the SLC family members most closely linked to PDAC patient outcomes. Using in vitro and in vivo experiments along with multi‑omics approaches, we further clarified its functional roles in stromal-immune-metabolic networks within the TME. Following virtual screening of a million‑compound library and validated by binding assays, two target‑specific inhibitors were identified. Using pharmacological and genetic methods, the therapeutic potential of targeting this pathway was systematically evaluated. SLC6A14 is identified as a prognostic biomarker and functional driver of PDAC progression, with higher expression levels correlating with poor patient outcomes; it facilitates tumor growth by modifying amino acid metabolic reprogramming and exerting immunosuppressive effects by competitively impairing amino acid uptake in dendritic cells and CD8⁺ T cells. STOCK1N-75990 is a specific SLC6A14 inhibitor that competitively blocks amino acid binding, induces intracellular nutrient deprivation, and causes profound metabolic collapse; it exhibits marked anti-tumor activity and limited toxicity in preclinical models, synergizing with anti-PD1 therapy. These findings establish SLC6A14 as a potent multifunctional therapeutic target and demonstrate the clinical relevance of its inhibitors as a metabolic immunotherapy for PDAC.