The study by He et al. identifies the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex as a therapeutic target in POU2F3-driven small cell lung cancer (SCLC) and POU2AF1-dependent B cell malignancies. The mSWI/SNF complex is epigenetically dependent in SCLC-P, where it modulates chromatin accessibility and supports oncogenic signaling through the POU2F3 complex. Treatment with an orally bioavailable mSWI/SNF ATPase degrader, AU-24118, effectively degrades the mSWI/SNF complex, leading to chromatin eviction of POU2F3 and its coactivators, and significant tumor growth inhibition in preclinical models of SCLC-P. Additionally, AU-24118 shows potent anti-tumor efficacy in multiple myeloma (MM) models, where it degrades the mSWI/SNF complex and impairs IRF4 signaling. These findings suggest that targeting the mSWI/SNF complex represents a promising therapeutic strategy for POU2F-POU2AF-driven malignancies, with potential for improved patient outcomes.The study by He et al. identifies the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex as a therapeutic target in POU2F3-driven small cell lung cancer (SCLC) and POU2AF1-dependent B cell malignancies. The mSWI/SNF complex is epigenetically dependent in SCLC-P, where it modulates chromatin accessibility and supports oncogenic signaling through the POU2F3 complex. Treatment with an orally bioavailable mSWI/SNF ATPase degrader, AU-24118, effectively degrades the mSWI/SNF complex, leading to chromatin eviction of POU2F3 and its coactivators, and significant tumor growth inhibition in preclinical models of SCLC-P. Additionally, AU-24118 shows potent anti-tumor efficacy in multiple myeloma (MM) models, where it degrades the mSWI/SNF complex and impairs IRF4 signaling. These findings suggest that targeting the mSWI/SNF complex represents a promising therapeutic strategy for POU2F-POU2AF-driven malignancies, with potential for improved patient outcomes.