EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion

Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY, producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP inhibitors. Defective HRR contributes to a high tumor mutational burden that, in turn, is expected to prompt an innate immune response. Notably, EMSY accumulation suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways, individually or in combination, represents a therapeutic strategy in NSCLC patients harboring alterations in KEAP1.

Automated summary

NSCLCs with KEAP1 mutations show resistance to immunotherapy due to EMSY accumulation suppressing immune response. KEAP1 loss results in stabilized EMSY, causing HRR defects and sensitivity to PARP inhibitors. The accumulation of EMSY impairs immune signaling and promotes immune evasion. Activation of the type I interferon response using a STING agonist inhibits KEAP1-mutant tumor growth, suggesting a potential therapeutic strategy for NSCLC patients with KEAP1 alterations.