In sum, we propose a model by which MYC-NOTCH2-REST can promote the evolution of an immune-inflamed, non-NE-enriched, ICB-nonresponsive subset, whereas NOTCH1 activation induces intratumor heterogeneity of ASCL1 and NEUROD1 NE-enriched SCLC with high EMT, STING, and CD8+ T cell infiltration, thereby favoring survival with ICB. Here, ASCL1 is linked to small cell lung carcinoma.