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.
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.
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