Oxaliplatin accelerates immunogenic cell death by activating the cGAS/STING/TBK1/IRF5 pathway in gastric cancer

Immunogenic cell death is a tumor cell death involving both innate and adaptive immune responses. Given the published findings that oxaliplatin causes the secretion of high mobility group box 1 (HMGB1) from Cancer cells, which is necessary for the initiation of immunogenic cell death, we investigated whether oxaliplatin plays an Anticancer role in gastric Cancer by inducing immunogenic cell death and further explored its mechanism. We found that oxaliplatin inhibited viability and induced Pyroptosis, immunogenic cell death, the production of Reactive Oxygen Species, mitochondrial permeability transition pore (mPTP) opening, and Cyclic GMP-AMP Synthase (cGAS)-stimulator of interferon genes (STING) axis activation in gastric Cancer cells. Suppressing mPTP opening (cyclosporine treatment), depleting mitochondrial DNA (mtDNA; ethidium bromide treatment), or STING downregulation (H151 or si-STING treatment) reversed cGAS/STING pathway activation and the increased immunogenic cell death induced by oxaliplatin in MKN-45 and AGS cells. Moreover, oxaliplatin induced immunogenic cell death via activating the cGAS/STING/TANK-binding kinase 1 (TBK1; also known as serine/threonine-protein kinase TBK1)/interferon regulatory factor 5 (IRF5) pathway. In conclusion, oxaliplatin treatment could induce immunogenic cell death and mPTP opening and activate the cGAS/STING/TBK1/IRF5 pathway in gastric Cancer cells.

cGAS/STING/TBK1/IRF5 pathway; gastric cancer; immunogenic cell death; mPTP opening; oxaliplatin.