Effective targeted therapies remain a major challenge for patients with small cell lung cancer (SCLC). Targeting the epigenome of SCLC to address immune evasion and chemoresistance offers a promising strategy to improve treatment outcomes. In this study, we investigate the role of Polycomb repressive complex 2 (PRC2), a major transcriptional repressor, by distinguishing its structural versus enzymatic functions. Conditional deletion of Eed, a core structural component of PRC2, prevented tumor formation in an autochthonous SCLC model. In contrast, enzymatic inhibition of EZH2 did not alter tumor growth. However, EZH2 inhibition significantly altered its interactome, revealing novel targets for drug development. Given that EZH2 inhibitors are clinically approved for other cancers, we conducted a focused drug screen to improve the therapeutic potential of EZH2. We found that prolonged EZH2 inhibition sensitized neuroendocrine cancer cells to G9a/GLP inhibition. Transcriptomic analysis revealed that this combination induced an oxidative stress response by modulating the expression of cellular oxidases, an effect that could be reversed by antioxidant treatment. These results highlight the critical role of PRC2 structural activity in SCLC and identify promising drug combinations to enhance the efficacy of EZH2 inhibitors.