Abstract
BACKGROUND: Carbonic anhydrase 9 (CA9) plays a crucial role in pH regulation and adaptation under hypoxic conditions in the tumor microenvironment. Despite its known involvement in the progression of specific cancers, a comprehensive pan-cancer examination of the prognostic value and biological implications of CA9 has not been performed. This study systematically explored the diverse roles of CA9 across multiple cancer types. METHODS: Bioinformatics methods were applied via extensive datasets from TCGA, GTEx, CPTAC, CancerSEA, and the public literature. We systematically analyzed the associations between CA9 expression profiles and various clinical parameters, prognosis, immune infiltration, immune-related genes, TMB, MSI, and tumor stemness scores. Additionally, a single-cell functional analysis was conducted. RESULTS: CA9 was significantly upregulated in 29 out of 33 cancer types, indicating high discriminatory ability between tumor and normal tissues. Elevated CA9 expression correlated with poor OS and PFIs in multiple cancers, such as GBMLGG, CESC, LUAD, KIPAN, GBM, THYM, LIHC, THCA, PAAD, and KICH. In 39 cancers, CA9 expression was predominantly negatively correlated with the infiltration of 22 immune cell infiltrations. It was also associated with TMB in 12 tumors and with MSI in 9. Single-cell analysis revealed positive links between CA9 and essential processes such as hypoxia, metastasis, angiogenesis, and stemness. CONCLUSION: This study provides compelling evidence that CA9 is a potential pan-cancer prognostic marker and diagnostic tool. The associations of CA9 with immune components and determinants of immunotherapy response indicate the importance of CA9 in advancing cancer research and personalized treatment strategies.