The role of carbonic anhydrases IX and XII in hypoxia-driven tumor adaptation and chemoresistance: an underexplored frontier for novel therapeutic strategies in ovarian cancer

Human carbonic anhydrases IX and XII (hCA IX/XII) regulate pH homeostasis and may facilitate tumor adaptation, progression, and therapeutic resistance. Although extensively studied in other malignancies, their roles in ovarian cancer (OC) remain insufficiently characterized. This narrative review critically examines their biological functions and therapeutic potential, emphasizing hypoxia and acidosis within the heterogeneous ovarian tumor microenvironment. Literature was searched in PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, prioritizing studies on hypoxia, acidosis, chemoresistance, and carbonic anhydrase inhibition. Evidence from OC models was distinguished from findings in other cancers. Public transcriptomic data were additionally explored using GEPIA and Kaplan–Meier Plotter to examine CA9 and CA12 expression and survival associations. Available findings suggest potential roles for these isoenzymes in adaptation to acidic, hypoxic conditions, but OC-specific mechanistic and therapeutic evidence remains limited. We discuss preclinical inhibitors, key knowledge gaps, and priorities for future research.