Decoding the tumor immune microenvironment in lung squamous cell carcinoma: characteristics, regulatory mechanisms, and future directions in immunotherapy

Lung squamous cell carcinoma (LUSC), a predominant type of lung cancer, is marked by an unfavorable prognosis and limited therapeutic options. Unlike lung adenocarcinoma (LUAD), LUSC exhibits few driver mutations, resulting in minimal benefits from targeted therapies for these patients. Despite the transformative effects of immunotherapy on patient outcomes, only a subset of patients achieving durable responses. This heterogeneity in treatment outcomes is increasingly attributed to the complex feature of the tumor immune microenvironment (TIME) in LUSC. The TIME of LUSC is a highly dynamic ecosystem composed of diverse immune cell populations and stromal components that collectively foster an immune-evasive niche. Recent breakthroughs in multi-omics technologies, particularly single-cell RNA sequencing (scRNA-seq) and spatial omics, have provided unprecedented resolution in dissecting the cellular and molecular architecture of the TIME in LUSC. These technologies have enabled the identification of distinct immune cells and their spatial interactions with the tumor, shedding light on the mechanisms underlying immune evasion and resistance to immunotherapy. Building on these advancements, this review establishes a new classification of the TIME which may guide patient stratification and personalized immunotherapy. And we comprehensively offer a detailed examination of the principal characteristics and regulatory mechanisms of the TIME, highlighting potential immunotherapeutic strategies tailored to this distinct immunological context.