Claudin-9 ( promotes gastric cancer progression by enhancing the glycolysis pathway and facilitating PD-L1 lactylation to suppress CD8 T cell anti-tumor immunity.

BACKGROUND

Gastric cancer (GC) is a common malignancy characterized by the absence of reliable prognostic indicators and effective therapeutic targets. Claudin-9 (CLDN9) has been demonstrated to be upregulated in various cancers. However, its prognostic value, biological function, and regulatory mechanisms in GC remain unclear. Therefore, this study aimed to elucidate the role of in GC progression and its underlying mechanisms.

METHODS

We utilized consensus cluster, random survival forest, and multivariate Cox regression analyses to identify in GC. Subsequently, we evaluated the mRNA and protein levels of in GC using quantitative real-time polymerase chain reaction (PCR) (qRT-PCR), Western blotting (WB), and immunohistochemistry (IHC). Furthermore, the role of in GC progression was investigated using a series of functional and experiments. Finally, we elucidated the molecular mechanisms of using bioinformatics, molecular biology, animal models, and patient tissue specimens.

RESULTS

Two GC subtypes with survival and functional differences were identified based on glycolytic metabolic genes in the Cancer Genome Atlas (TCGA)- Stomach adenocarcinoma (STAD) dataset. A prognostic risk score was calculated using seven genes to assess the overall survival (OS) in GC. Using random survival forest and multivariate Cox analyses, we identified as the key gene linked to the glycolytic subtype and prognosis of GC. expression was significantly upregulated in patients with GC as well as in GC cells. knockdown inhibited tumor proliferation, invasion, and metastasis both and . Mechanistically, was found to regulate lactate dehydrogenase A (LDHA) expression and promote glycolytic metabolism by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/hypoxia-inducible factor 1-alpha (HIF1α) signaling pathway. Additionally, lactate, a glycolytic metabolite, enhanced programmed cell death ligand 1 (PD-L1) lactylation and stability, which suppressed anti-tumor immunity in CD8 T cells, thereby contributing to GC progression.

CONCLUSIONS

expression is associated with GC development and progression. Mechanistically, enhances the glycolysis pathway and facilitates PD-L1 lactylation through the PI3K/AKT/HIF1α signaling pathway, thereby suppressing anti-tumor immunity in CD8 T cells. has the potential to serve as a novel prognostic marker and therapeutic target for GC.