Targeting SLC6A14-mediated nutrient competition reverses an immunosuppressive metabolic niche in pancreatic cancer.
9 affiliations
- 1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310000, Zhejiang, China.
- 2Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
- 3Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
- 4MOE Joint International Research Laboratory of Pancreatic Diseases, Hangzhou, Zhejiang, China.
- 5Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
- 6Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310000, Zhejiang, China. [email protected].
- 7Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. [email protected].
- 8Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China. [email protected].
- 9MOE Joint International Research Laboratory of Pancreatic Diseases, Hangzhou, Zhejiang, China. [email protected].
Abstract
Background
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.Methods
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.Results
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.Conclusion
These findings establish SLC6A14 as a potent multifunctional therapeutic target and demonstrate the clinical relevance of its inhibitors as a metabolic immunotherapy for PDAC.
Related
- Precision Targeting of Heparan Sulfate Proteoglycans Broadly Dysregulates Survival Signaling and Metabolic Adaptation in Pancreatic Cancer
- KRAS-driven metabolic reprogramming of enhanced MFSD2A-mediated lysophosphatidylcholine scavenging promotes survival and progression of pancreatic ductal adenocarcinoma
- Multi-omics and functional analysis of a bioengineered vascularized pancreatic cancer model reveal an immunosuppressive and therapy-resistant niche
- Disruption of ACTG1 potentiates anti-TIM-3 immunotherapy by reprogramming the immunosuppressive microenvironment via the CSF3/CSF3R axis in pancreatic cancer
- Metabolic Competition-Driven Antitumor Immunity of glpX-Deficient Engineered Salmonella via Glucose Deprivation and STING Activation in Bladder Cancer
BibTeX
@article{he2026targeting,
title = {{Targeting SLC6A14-mediated nutrient competition reverses an immunosuppressive metabolic niche in pancreatic cancer.}},
author = {Lihong He and Zihao Lin and Lingyue Liu and Shicheng Yao and Jiawei Wang and Jingpeng Guo and Changxin Zhong and Hanjia Zhang and Xiaozhen Zhang and Tingbo Liang and Xueli Bai},
journal = {Experimental hematology \& oncology},
year = {2026},
month = aug,
doi = {10.1186/s40164-026-00818-9},
url = {https://europepmc.org/article/MED/42963794},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Targeting SLC6A14-mediated nutrient competition reverses an immunosuppressive metabolic niche in pancreatic cancer.
AU - Lihong He
AU - Zihao Lin
AU - Lingyue Liu
AU - Shicheng Yao
AU - Jiawei Wang
AU - Jingpeng Guo
AU - Changxin Zhong
AU - Hanjia Zhang
AU - Xiaozhen Zhang
AU - Tingbo Liang
AU - Xueli Bai
PY - 2026
DA - 2026/08/14
JO - Experimental hematology & oncology
DO - 10.1186/s40164-026-00818-9
UR - https://europepmc.org/article/MED/42963794
AB - Background 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.Methods 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.Results 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.Conclusion These findings establish SLC6A14 as a potent multifunctional therapeutic target and demonstrate the clinical relevance of its inhibitors as a metabolic immunotherapy for PDAC.
SN - 2162-3619
ER -