An emerging approach for treating cancer involves programming patient-derived T cells with genes encoding disease-specific chimeric antigen receptors (CARs), so that they can combat tumour cells once they are reinfused. Although trials of this therapy have produced impressive results, the in vitro methods they require to generate large numbers of tumour-specific T cells are too elaborate for widespread application to treat cancer patients. Here, we describe a method to quickly program circulating T cells with tumour-recognizing capabilities, thus avoiding these complications. Specifically, we demonstrate that DNA-carrying nanoparticles can efficiently introduce leukaemia-targeting CAR genes into T-cell nuclei, thereby bringing about long-term disease remission. These polymer nanoparticles are easy to manufacture in a stable form, which simplifies storage and reduces cost. Our technology may therefore provide a practical, broadly applicable treatment that can generate anti-tumour immunity ‘on demand’ for oncologists in a variety of settings.

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, encoding an acetyltransferase, is among the most frequently mutated genes in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report acceleration of SCLC upon inactivation in an autochthonous mouse model. Extending these observations beyond the lung, broad deletion in mouse neuroendocrine cells cooperated with loss to promote neuroendocrine thyroid and pituitary carcinomas. Gene expression analyses showed that loss results in reduced expression of tight junction and cell adhesion genes, including , across neuroendocrine tumor types, whereas suppression of promoted transformation in SCLC. and other adhesion genes exhibited reduced histone acetylation with inactivation. Treatment with the histone deacetylase (HDAC) inhibitor Pracinostat increased histone acetylation and restored CDH1 expression. In addition, a subset of -deficient SCLC exhibited exceptional responses to Pracinostat Thus, CREBBP acts as a potent tumor suppressor in SCLC, and inactivation of CREBBP enhances responses to a targeted therapy. Our findings demonstrate that CREBBP loss in SCLC reduces histone acetylation and transcription of cellular adhesion genes, while driving tumorigenesis. These effects can be partially restored by HDAC inhibition, which exhibited enhanced effectiveness in -deleted tumors. These data provide a rationale for selectively treating-mutant SCLC with HDAC inhibitors. .