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40 reviewsNSD2 catalyses the epigenetic modifcation H3K36me2 (refs. 1,2) and is a candidate convergent downstream efector of oncogenic signalling in diverse malignancies3–5. However, it remains unclear whether the enzymatic activity of NSD2 is therapeutically targetable. Here we characterize a series of clinical-grade small-molecule catalytic NSD2 inhibitors (NSD2i) and show that the pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efcacy in KRASdriven preclinical cancer models. NSD2i inhibits NSD2 with single-digit nanomolar half-maximal inhibitory concentration potency and high selectivity over related methyltransferases. Structural analyses reveal that the specifcity of NSD2i for NSD2 is due to competitive binding with S-adenosylmethionine and catalytic disruption through a binary-channel obstruction mechanism. Proteo-epigenomic and singlecell strategies in pancreatic and lung cancer models support a mechanism in which sustained NSD2i exposure reverses pathological H3K36me2-driven chromatin plasticity, re-establishing silencing at H3K27me3-legacy loci to curtail oncogenic gene expression programs. Accordingly, NSD2i impairs the viability of pancreatic and lung cancer cells and the growth of patient-derived xenograft tumours. Furthermore, NSD2i, which is well-tolerated in vivo, prolongs survival in advancedstage autochthonous KRASG12C-driven pancreatic and lung tumours in mouse models to a comparable level as KRAS inhibition with sotorasib6. In these models, treatment with both a NSD2 inhibitor and sotorasib synergize to confer sustained survival with extensive tumour regression and elimination. Together, our work uncovers targeting of the NSD2–H3K36me2 axis as an actionable vulnerability in difcult to treat cancers and provides support for the evaluation of NSD2 and KRAS inhibitor combination therapies in a clinical setting.