Antibody-drug conjugates and radioconjugates targeting carbonic anhydrase IX and XII in hypoxic tumors: Bench to clinical applications.

Treating hypoxic tumors is challenging due to their aggressive nature, resistance to standard treatments, often leading to poor outcomes. Hypoxic tumors create a unique environment that reduces the effectiveness of traditional treatments such as chemotherapy and radiotherapy. Human carbonic anhydrases (hCA IX and hCA XII) are involved in tumors survival and metabolism by regulating pH homeostasis, ferroptosis, metastatization, and other processes. Developing drugs that specifically target these enzymes has been demonstrated to disrupt the tumor survival mechanisms, leading to significant antitumor effects. This review discusses recent developments on antibody-drug conjugates (ADCs) and radioconjugates targeting hCA IX and hCA XII in hypoxic tumors. New approaches based on small molecule inhibitors and monoclonal antibodies such as girentuximab provided encouraging results in preclinical research and clinical trials. These advances highlight the potential of hCA-targeted therapies to improve cancer treatment for hypoxic tumors.