biostudies-literatureKuchuk OItalian Ministry of HealthAssociazione Italiana Ricerca sul Cancroe1445452https://www.ebi.ac.uk/biostudies/studies/S-EPMC5993489biostudies-literatureUnknown7(7)Interfering with tumor metabolism is an emerging strategy for treating cancers that are resistant to standard therapies. Featuring a rapid proliferation rate and exacerbated glycolysis, hepatocellular carcinoma (HCC) creates a highly hypoxic microenvironment with excessive production of lactic and carbonic acids. These metabolic conditions promote disease aggressiveness and cancer-related immunosuppression. The pH regulatory molecules work as a bridge between tumor cells and their surrounding milieu. Herein, we show that the pH regulatory molecules CAIX, CAXII and V-ATPase are overexpressed in the HCC microenvironment and that interfering with their pathways exerts antitumor activity. Importantly, the V-ATPase complex was expressed by M2-like tumor-associated macrophages. Blocking <i>ex viOncoimmunologypH regulators to target the tumor immune microenvironment in human hepatocellular carcinoma.PMC5993489CC IG-15192LR IG-1428552/RF-2010-2312620Huber VRivoltini LKuchuk OVilla AAlison MRTuccitto ACitterio DMazzaferro VVergani BMilione MCarradori SCastelli CCamisaschi CSupuran CTfalsepH regulators to target the tumor immune microenvironment in human hepatocellular carcinoma.Interfering with tumor metabolism is an emerging strategy for treating cancers that are resistant to standard therapies. Featuring a rapid proliferation rate and exacerbated glycolysis, hepatocellular carcinoma (HCC) creates a highly hypoxic microenvironment with excessive production of lactic and carbonic acids. These metabolic conditions promote disease aggressiveness and cancer-related immunosuppression. The pH regulatory molecules work as a bridge between tumor cells and their surrounding milieu. Herein, we show that the pH regulatory molecules CAIX, CAXII and V-ATPase are overexpressed in the HCC microenvironment and that interfering with their pathways exerts antitumor activity. Importantly, the V-ATPase complex was expressed by M2-like tumor-associated macrophages. Blocking <i>ex vi2018-01-01T00:00:00Z20182025-04-25T21:17:11.814Z2019-03-26T23:41:41ZS-EPMC59934892990005510.1080/2162402X.2018.1445452