Introduction Gastric cancer remains one of the most lethal malignancies worldwide. The tumour microenvironment (TME)—particularly cancer-associated fibroblasts (CAFs)—plays a critical role in tumour progression, immune evasion, and resistance to immunotherapy.
Introduction
Gastric cancer remains one of the most lethal malignancies worldwide. The tumour microenvironment (TME)—particularly cancer-associated fibroblasts (CAFs)—plays a critical role in tumour progression, immune evasion, and resistance to immunotherapy. Although immune checkpoint inhibitors (ICIs) have improved outcomes in some patients with gastric cancer, many fail to respond due to a highly immunosuppressive TME. Understanding the specific fibroblast subpopulations responsible for immune suppression may help identify new therapeutic targets.
Summary
In this study, researchers used single-cell RNA sequencing and spatial transcriptomics from gastric cancer tissues to identify a distinct fibroblast subset characterized by phosphodiesterase type 5A (PDE5A) expression.
Key findings include:
PDE5A⁺ CAFs were associated with poorer overall survival and a strongly immunosuppressive tumour microenvironment.
These fibroblasts promoted extracellular matrix remodeling and epithelial–mesenchymal transition (EMT) in gastric cancer cells.
PDE5A⁺ CAFs activated the PI3K/AKT/mTOR pathway, leading to secretion of CXCL12, which interacts with CXCR4 to recruit dysfunctional CD8⁺ TEX⁺ LAG3 T cells, thereby suppressing effective anti-tumor immunity.
Tumors enriched with PDE5A⁺ CAFs showed T-cell exclusion and reduced cytotoxic CD8⁺ T-cell infiltration, contributing to immunotherapy resistance.
Importantly, combined therapy using a PDE5A inhibitor (vardenafil) with LAG3 immune checkpoint blockade significantly improved antitumor responses and reduced tumor growth in mouse models.
Key Message
PDE5A⁺ cancer-associated fibroblasts represent a critical driver of immune suppression in gastric cancer, and targeting this pathway may enhance the effectiveness of immunotherapy.
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