Carbonic Anhydrase IX: A Renewed Target for Cancer Immunotherapy

SIMPLE SUMMARY: Carbonic anhydrase IX (CAIX) has been explored for a long time as a therapeutic target in the fight against clear cell renal cell carcinoma and several hypoxic tumors, usually offering modest results followed by adverse effects. However, recent studies using different antibodies and adoptive cell therapies against CAIX have generated exciting prospects for the immunotherapy of these tumors. This complete review will approach the past and future of anti-CAIX immunotherapies. ABSTRACT: The carbonic anhydrase isoform IX (CAIX) enzyme is constitutively overexpressed in the vast majority of clear cell renal cell carcinoma (ccRCC) and can also be induced in hypoxic microenvironments, a major hallmark of most solid tumors. CAIX expression is restricted to a few sites in healthy tissues, positioning this molecule as a strategic target for cancer immunotherapy. In this review, we summarized preclinical and clinical data of immunotherapeutic strategies based on monoclonal antibodies (mAbs), fusion proteins, chimeric antigen receptor (CAR) T, and NK cells targeting CAIX against different types of solid malignant tumors, alone or in combination with radionuclides, cytokines, cytotoxic agents, tyrosine kinase inhibitors, or immune checkpoint blockade. Most clinical studies targeting CAIX for immunotherapy were performed using G250 mAb-based antibodies or CAR T cells, developed primarily for bioimaging purposes, with a limited clinical response for ccRCC. Other anti-CAIX mAbs, CAR T, and NK cells developed with therapeutic intent presented herein offered outstanding preclinical results, justifying further exploration in the clinical setting.