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.
Competing Interests: Declaration of interests T.P. has received Honoraria/Consulting fees from Calithera Biosciences and Vividion Therapeutics and research support from Bristol Myers Squibb, Dracen Pharmaceuticals, and Agios Pharmaceuticals. M.P. is a cofounder of Coho Therapeutics. He is also a consultant for, a member of the scientific advisory board of, and has financial interests in Coho Therapeutics, CullGen, Kymera Therapeutics, Santi Therapeutics, and SEED Therapeutics. The other authors declare no competing interests.
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