Carbonic Anhydrases in Sarcoma: Resetting the Tumor's Survival Script

ABSTRACT

Carbonic anhydrases (CA) are zinc‐containing metalloenzymes that catalyze the reversible hydration of carbon dioxide, playing a central role in pH homeostasis. In aggressive sarcomas, including osteosarcoma and Ewing sarcoma, specific CA isoforms are exploited to establish a pH gradient characterized by an alkaline cytoplasm and acidic extracellular microenvironment. This gradient promotes tumor cell survival under hypoxia, facilitates invasion and metastasis, and drives resistance to conventional therapies. High levels of CA II and CA IX expression are associated with worse 5‐year survival in patients diagnosed with Ewing Sarcoma and osteosarcoma, respectively. Carbonic anhydrase inhibitors have evolved from non‐selective sulfonamides to isoform‐selective agents, such as the clinically advanced SLC‐0111, which preferentially targets CA IX. Beyond direct cytotoxicity, carbonic anhydrase inhibitors exert multifaceted antitumor effects: they reverse pathological pH gradients, overcome pH‐dependent chemoresistance, suppress invasive potential, and induce distinct cell death pathways including apoptosis and ferroptosis. Thus, CA inhibitors hold considerable promise for use in combination therapy, especially chemotherapy and immunotherapy. Clinical trials of CA inhibitors in advanced solid tumors have established favorable safety profiles, supporting their evaluation in CA‐enriched sarcoma populations. This review summarizes the mechanistic rationale for targeting carbonic anhydrases in osteosarcoma and Ewing sarcoma, highlighting the therapeutic potential of CA inhibitors as part of combination regimens to overcome treatment resistance and improve patient outcomes.