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 tumor microenvironment (TME). This niche is critically regulated by hypoxia-inducible carbonic anhydrase (CA) isoforms IX and XII. These enzymes catalyze extracellular carbon dioxide hydration, acidifying the milieu to promote invasion, metastasis, and immune evasion. Pharmacological CA IX/XII inhibition counteracts this by normalizing pH, reducing invasiveness, and reinvigorating anti-tumor immunity. Oncolytic viruses (OVs) represent a complementary immunotherapeutic modality. Engineered to selectively replicate in tumor 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 tumor 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 defenses. Preclinical evidence supports that this multimodal approach enhances tumor regression, suppresses metastasis, and prolongs survival, offering a promising translational paradigm for GI cancers.
Reza Zolfaghari Emameh (Sun,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: