Inhibition of IDH3α Enhanced the Efficacy of Chemoimmunotherapy by Regulating Acidic Tumor Microenvironments

SIMPLE SUMMARY: Isocitrate dehydrogenase 3α (IDH3α) is highly expressed in many cancers and is associated with poor patient prognosis. However, it is not clear whether the aberrant expression of IDH3α is related to the efficacy of chemoimmunotherapy against cancer. We used in vivo and in vitro experiments and bioinformatics to explore the potential role of IDH3α in chemoimmunotherapy treatment. Our results indicate that IDH3α overexpression leads to resistance to chemoimmunotherapy by regulating the acidic tumor microenvironments and the cGAS–STING pathway. Our results provide initial preclinical evidence that the combination of IDH3α knockdown and chemoimmunotherapy may improve the therapy for cancer patients. ABSTRACT: In recent years, chemoimmunotherapy has become effective in some advanced cancers, but its effect is still limited. Transcriptional upregulation of isocitrate dehydrogenase 3α (IDH3α) can promote tumor initiation and progression. However, it is not clear whether the aberrant expression of IDH3α is related to the efficacy of chemoimmunotherapy in cancers. Here, we found that IDH3α was elevated in uterine cervical cancer (UCC) and lung adenocarcinoma (LUAD) samples by using public databases. High expression of IDH3α could promote the epithelial–mesenchymal transition (EMT), alter the intracellular redox status, promote glycolysis, and induce an acidic microenvironments in cancer cells. Furthermore, we found that inhibition of IDH3α combined with chemoimmunotherapy (cisplatin and programmed cell death ligand 1 (PD-L1) antibodies) activated the cGAS–STING pathway, promoted CD8(+) T cell infiltration, and decreased tumor growth in mouse models of cervical cancer. In conclusion, our data indicate that silencing IDH3α sensitizes tumors to chemoimmunotherapy by modulating the acidic microenvironment and activating the cGAS–STING pathway.