The hyperactive variant, NSD2E1099K, cooperates with oncogenic KRAS signaling to drive lung adenocarcinoma (LUAD) pathogenesis, whereas CRISPRi-mediated NSD2 inactivation strongly attenuates tumor progression of LUAD32, indicating that the NSD2-H3K36me2 axis sustains oncogenic signaling and could be a bona fide LUAD therapeutic target. Here, NSD2 is linked to lung adenocarcinoma.