Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma that is highly immune evasive and typically resistant to immune checkpoint blockade (ICB), despite a high mutational burden and the presence of numerous potential neoantigens. SCLC exhibits marked cellular plasticity, with tumour cells dynamically transitioning between neuroendocrine and non-neuroendocrine states. We have shown that in the neuroendocrine state, genes encoding MHC class I and other innate and adaptive immune ligands and receptors are epigenetically silenced. Transition to a non-neuroendocrine state reactivates these immune genes, leading to expression of an inflammatory gene signature associated with enhanced patient responses to ICB. Using targeted screening approaches, we have identified the key epigenetic regulatory complexes controlling SCLC plasticity. Inhibition of these complexes induces switching from a neuroendocrine to an inflammatory tumour cell state, leading to enhanced T cell mediated tumour clearance. Together, these findings provide a rationale for new therapeutic strategies combining epigenetic modulators with immune checkpoint blockade to overcome immunotherapy resistance in SCLC.