Carbonic Anhydrase Inhibitors in Oncology

Tumor hypoxia and extracellular acidosis are hallmarks of the tumor microenvironment that promote cancer progression, metabolic adaptation, and resistance to therapy. Among the molecular mediators of these processes, carbonic anhydrase IX (CA IX) and carbonic anhydrase XII (CA XII) play central roles in maintaining intracellular pH homeostasis and facilitating tumor cell survival under hypoxic stress, making them highly attractive targets for selective therapeutic intervention. This has prompted an effort to inhibit specific CA isoforms, as an anticancer therapeutic strategy with small molecule inhibitors, one of which (SLC-0111) completed Phase I clinical trials. However, other CA isoforms also show similar activity and tissue distribution in cancers and have not been considered as therapeutic targets for cancer treatment. Recent findings have revealed that CA IX and CA XII are not only critical for pH regulation but also intersect with key metabolic and redox pathways, including ferroptosis, glutathione metabolism, and mitochondrial iron-sulfur cluster biogenesis. Parallel advances in drug design have expanded this therapeutic paradigm through the development of dual-target inhibitors, combining CA IX/XII inhibition with modulation of other cancer-associated pathways. Beyond small-molecule inhibitors, antibody-based approaches have reached clinical and preclinical development as imaging agents, radioimmunotherapeutics, antibody-drug conjugates, and nanomaterial conjugates. Collectively, these strategies highlight the potential of exploiting the metabolic vulnerabilities of hypoxic tumors by co-targeting CA IX/XII with complementary redox or survival pathways, paving the way toward rational polypharmacology in precision oncology.