Integrated Multi-omics Profiling Reveals Microenvironmental Remodeling as a Key Driver of House Dust Mite Induced Lung Cancer Progression

Chronic exposure to house dust mite (HDM) induces lung inflammation and DNA damage, but its impact on lung tumor progression and mutagenesis remains largely unexplored.HDM exposure promoted tumor growth without significantly altering mutational burden in vitro or in vivo. Transcriptomic analysis revealed tissue-specific effects: in normal lung tissue, HDM enhanced pro-inflammatory and immune activation programs (e.g., neutrophil degranulation, Fc receptor signaling, and B cell receptor pathways) and increased Th1, Th2, and Th17-associated pathways, while DNA methylation analysis showed promoter hypermethylation of other immune-related genes, strongly anti-correlated with their expression, indicating a complex, gene-specific regulatory response. In tumors, HDM suppressed T cell responses, adaptive immunity, antigen presentation, and chemokine-mediated immune trafficking. Tumor DNA methylation patterns remained largely static, consistent with pre-existing epigenetic silencing, while immune deconvolution further indicated a shift toward a myeloid-dominant, immunosuppressive tumor microenvironment (TME) with reduced cytotoxic T cell and NK infiltration. Notably, the pro-tumorigenic effect of HDM exposure was maintained in IL-1b-deficient mice but was almost completely inhibited in IL-17A-deficient mice, highlighting a key role for IL-17A in mediating HDM-driven tumor promotion.These findings suggest that HDM accelerates lung tumor progression primarily through non-mutagenic, immune-mediated mechanisms. Chronic exposure promotes tumor growth via immune reprogramming, myeloid skewing, and epigenetic suppression of immune responses, creating an immunosuppressive TME. Collectively, this work highlights how chronic aeroallergen exposure shapes the lung microenvironment to favor tumor progression and underscores the importance of targeting microenvironmental remodeling in environmentally influenced cancers