Inhibition of IDH3α enhanced the efficacy of chemoimmunotherapy by activating cGAS-STING pathway through regulating acidic tumor microenvironments

Abstract Chemoimmunotherapy is the treatment of choice for some advanced progressive cancers, but it is only effective in a small subset of patients. Transcriptional upregulation of isocitrate dehydrogenase 3α (IDH3α) promoted cancer progression through metabolic reprogramming. Here, we demonstrated that IDH3α is elevated in uterine cervical cancer (UCC) and non-small cell lung cancer (NSCLC) patient samples and promotes epithelial-mesenchymal transition (EMT) in cervical cancer cells. Silencing IDH3α inhibited α-ketoglutarate production and glycolysis and reduced lactate release. In addition to regulating the acidic microenvironment, IDH3α activates the cGAS-STING pathway after treatment with cisplatin and programmed cell death ligand 1 (PD-L1) antibody in vivo and promotes CD8 + T cell infiltration and cytokine release. In conclusion, our data demonstrated that silencing IDH3α sensitizes chemoimmunotherapy by modulating the acidic microenvironment and activating the cGAS-STING pathway, which aims to improve the efficacy of chemoimmune-based combination therapy for patients with limited resistance.