In summary, we observed the ER stress response induced by IS in NSCLC for the first time, and our results showed that IS might enhance cisplatin-induced apoptosis by promoting ER stress, in which the PERK, IRE1α, ATF6 and PERK-eIF2α-ATF4-CHOP pathways were activated. Here, ATF4 is linked to non-small cell lung carcinoma.