In this trial, SMET12 plus toripalimab and chemotherapy achieved an ORR of 22.2% and median PFS of 4.2 months among driver gene-negative, advanced NSCLC patients following resistance to first-line immune checkpoint inhibitors-based therapy, and our findings showed that immunotherapy re-challenge regimens (anti-PD-1 agent plus SMET12 and chemotherapy) failed to overcome the acquired resistance to immunotherapy among refractory NSCLC patients. This evidence concerns the gene PDCD1 and non-small cell lung carcinoma.