Carbonic anhydrase IX and XII

The membrane-associated carbonic anhydrases (CAs) IX and XII have emerged as critical players in cancer biology due to their significant expression in various malignancies. The two enzymes differ in catalytic efficiency, with CA IX acting as a highly efficient catalyst while CA XII possesses moderate catalytic activity, and although both form a dimer, their resulting structural arrangement is diverse. Regarding their regulatory mechanisms, CA IX expression is primarily driven by the hypoxia-inducible factor 1 pathway in hypoxic microenvironments, whereas CA XII exhibits a more complex, context-dependent expression profile modulated by both hypoxia and estrogen receptor signaling. Both enzymes contribute to adaptation of tumor cells to acidic microenvironments and promote cancer progression. Considering this evidence, CA IX and CA XII represent attractive targets for modern oncology. This chapter comprehensively reviews their functional and structural properties and explores the most recent progresses in targeted intervention strategies highlighting the most promising approaches. Notably, while these enzymes exist as orthologs in other vertebrates, the scope of this chapter is restricted to human CA IX and CA XII, reflecting the overwhelming predominance of studies on the human isoforms in current literature.