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T cell activation and exhaustion are associated with highly coordinated changes in gene expression and chromatin accessibility. While the contribution of key, state-specific transcription factors to these processes has been extensively explored, the role for chromatin regulatory complexes remains less clear. The mammalian SWI/SNF (mSWI/SNF) complexes are a diverse family of ATP-dependent remodeling complexes that regulate DNA accessibility and hence facilitate timely and appropriate gene expression. Recent genome-scale CRISPR screens have highlighted the involvement of mSWI/SNF complexes in the acquisition of divergent T cell states; however, the mechanisms by which these complexes regulate T cell activation and exhaustion and how such activities may be leveraged for therapeutic benefit remain poorly understood. Here, we developed an in vitro system to map chromatin-level changes occurring during acute and chronic TCR stimulation in human T cells and to investigate the contribution of the mSWI/SNF complexes throughout these processes. By gene expression and chromatin profiling, we show that our in vitro model closely recapitulates the T cell activation and exhaustion phenotypes observed in human tumors. We demonstrate that the mSWI/SNF complexes contribute to shaping the epigenome of T cells at different activation and exhaustion stages, directing subsequent changes in gene expression. Specifically, deletion of components demarcating the cBAF subcomplex within the mSWI/SNF family improves T cell survival and proliferation and leads to the down-regulation of exhaustion hallmarks. Notably, by using four different compounds that either degrade or inhibit the catalytic activity of SMARCA2 and SMARCA4, we demonstrate that mSWI/SNF disruption significantly increases human T cell fitness, decreases exhaustion and is associated to memory-like hallmarks in chronically stimulated human T cells. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T fitness and expansion and results in improved anti-tumor control in vivo. These findings reveal a central role for mSWI/SNF complexes in the processes of T cell activation and exhaustion, and suggest SMARCA4/2 ATPase inhibitors and degraders as potential strategies to enhance current T-cell based cancer immunotherapies. Citation Format: Elena Battistello, Kimberlee Hixon, Dawn E. Comstock, Clayton K. Collings, Xufeng Chen, Javier Rodriguez Hernaez, Soobeom Lee, Konstantinos Ntatsoulis, Annamaria Cesarano, Kathryn Hockemeyer, W. Nicholas Haining, Matthew T. Witkowski, Jun Qi, Aristotelis Tsirigos, Fabiana Perna, Ioannis Aifantis, Cigall Kadoch. Targeting mammalian SWI/SNF chromatin remodeling complexes to improve T cell-based cancer immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1794.