CREBBP loss drives immune evasion by epigenetically silencing STING and MHC-I in small cell lung cancer.

Most small cell lung cancers (SCLCs) exhibit low immunogenicity and intrinsic resistance to immunotherapy, yet the underlying mechanisms remain poorly understood. Here, we identify CREBBP loss, a frequent genetic alteration in SCLC, as a key suppressor of tumor cell-intrinsic immune responses that drives an immune-cold tumor microenvironment in Rb1/Trp53-driven autochthonous mouse models. Consistently, Crebbp deletion promotes immune escape in syngeneic SCLC models. Mechanistically, Crebbp loss suppresses Sting and major histocompatibility complex class-I expression by reducing histone H3 acetylation. Notably, HDAC inhibition restores histone acetylation, reactivates these silenced genes, and induces tumor cell-intrinsic immune responses. Moreover, pharmacological HDAC inhibition synergizes with immune checkpoint blockade to suppress tumor growth in both Crebbp-mutant and Crebbp-wild-type SCLCs, with a more prominent effect in Crebbp-mutant tumors. Collectively, these findings establish CREBBP loss as a key mechanism of immune evasion and immunotherapy resistance in SCLC, highlighting HDAC inhibition as a promising strategy to enhance immunotherapy efficacy.