Dissecting the Immunological Profiles in -Amplified LUSC through Integrative Multi-Scale Analyses.

The histone H3 lysine 36 (H3K36) methyltransferase , a neighboring gene of , has been identified as a critical genetic driver of lung squamous cell carcinoma (LUSC). However, the molecular characteristics, especially the immunological roles of in driving carcinogenesis, are poorly understood. In this study, we systematically integrated multi-omics data (e.g., genome, transcriptome, proteome, and TMA array) to dissect the immunological profiles in -amplified LUSC. Next, pharmaco-transcriptomic correlation analysis was implemented to identify the molecular underpinnings and therapeutic vulnerabilities in LUSC. We revealed that -amplified LUSC presents a non-inflamed tumor immune microenvironment (TIME) state in multiple independent LUSC patient cohorts. Predictably, elevated expression was correlated with a worse immunotherapy outcome. Further molecular characterizations revealed that the high activity of unfolded protein response (UPR) signaling might be a pivotal mediator for the non-immunogenic phenotype of -amplified LUSC. Concordantly, we showed that -amplified LUSCs exhibited a more sensitive phenotype to compounds targeting UPR branches than the wild-type group. In brief, our multi-level analyses point to a previously unappreciated immunological role for and provide therapeutic rationales for -amplified squamous lung cancer.