Carbonic anhydrase modulation in the tumour microenvironment: synergistic pathways with oncolytic viruses in gastrointestinal malignancies.

Gastrointestinal (GI) malignancies are leading causes of global cancer mortality, with advanced stages showing pronounced therapeutic resistance. A key driver of this aggression is the immunosuppressive and acidic tumour microenvironment (TME). This niche is critically regulated by hypoxia-inducible carbonic anhydrase (CA) isoforms IX and XII. These enzymes catalyse extracellular carbon dioxide hydration, acidifying the milieu to promote invasion, metastasis and immune evasion. Pharmacological CA IX/XII inhibition counteracts this by normalising pH, reducing invasiveness and reinvigorating anti-tumour immunity. Oncolytic viruses (OVs) represent a complementary immunotherapeutic modality. Engineered to selectively replicate in tumour cells, OVs induce direct cytolysis and immunogenic cell death, thereby stimulating systemic immunity. However, their efficacy is hindered by the very acidosis sustained by CA activity. This establishes a compelling synergy: CA inhibition alleviates the acidic barrier to enhance OV spread and potency. Conversely, OV-mediated lysis disrupts hypoxic tumour regions, subsequently downregulating CA IX/XII expression and mitigating acidification. This bidirectional, self-reinforcing cycle positions their combination as a rational strategy to dismantle the TME's metabolic and immunological defences. Preclinical evidence supports that this multimodal approach enhances tumour regression, suppresses metastasis and prolongs survival, offering a promising translational paradigm for GI cancers.