All in all, we found that the activation of the MYC‐Notch‐non‐NE axis was connected to chemo‐resistance in ES‐SCLC, and DLL3, as a key inhibitory component of Notch signaling, served as a potent predictor for identifying patients who would benefit from chemo‐immunotherapy. This evidence concerns the gene DLL3 and small cell lung carcinoma.