Multi-omics profiling reveals mutant early-onset lung squamous cell carcinoma with a "hot" tumor immune microenvironment.

[BACKGROUND] Early-onset lung squamous cell carcinoma (LUSC) is a rare and poorly characterized entity. Its distinct clinicopathological, genomic, and tumor immune microenvironment (TIME) profiles remain to be elucidated. This study sought to explore the molecular landscape and immunophenotype of early-onset LUSC, with a focus on uncovering potential genomic associations with its clinical features.

[METHODS] In this retrospective, single-center cohort study, we conducted a comprehensive multi-omics analysis on patients with surgically resected, treatment-naïve early-onset LUSC (subjects aged ≤40 years, n=21) between 2015 and 2024 using whole-exome sequencing (WES) and digital spatial profiling (DSP). To contextualize our findings, we conducted a comparative analysis using publicly available LUSC data from The Cancer Genome Atlas (TCGA) via the Xena platform.

[RESULTS] WES revealed a high mutation frequency of (47.6%), which consistently co-occurred with mutation. Stratification by status identified two subgroups: CDKN2A-mutant (CDKN2A, n=10) and CDKN2A-wild-type (CDKN2A, n=11). The CDKN2A group exhibited more aggressive clinicopathological features, including higher Ki67 index and frequent vascular invasion, alongside a distinct genomic profile. Despite its aggressive phenotype, the CDKN2A group displayed a robust "hot" TIME, characterized by enriched cytotoxic and exhausted CD8 T cells, a higher intra-tumoral CD8/Foxp3 ratio, and significantly elevated programmed death-ligand 1 (PD-L1). Comparative analysis with public LUSC databases indicated that this specific immunogenic association was unique to the early-onset context and not observed in general LUSC populations. Patients in CDKN2A group showed a trend toward shorter overall survival (OS).

[CONCLUSIONS] Our study identifies mutation as a hallmark of a unique, aggressive yet immunogenic subtype of early-onset LUSC. This association appears to be specific to young patients, highlighting age of onset as a key biological variable. These findings provide a rationale for further investigation of status as a potential biomarker to guide immunotherapy strategies in early-onset LUSC.