Abstract An inverse association between asthma and several cancer types has been consistently observed across epidemiologic studies, yet the molecular mechanisms underlying this relationship remain unclear. To address this gap, we conducted a comprehensive genetic and functional analysis to identify variants, genes, and immune signaling pathways that may contribute to this protective association. From literature-validated genome-wide association studies, we compiled 246 asthma-associated SNPs and identified 14 variants that were also significantly associated with cancer risk. Notably, 11 of these SNPs demonstrated reversal directionality, where the asthma risk allele was associated with reduced cancer risk, particularly in glioma and colorectal cancer. Haplotype analysis further revealed 19 genes exhibiting diametric effects on asthma and cancer susceptibility. Among these, IL-9, TLR1, SMAD7, LPP, IL-7R, and HLA-DQB1 also showed inverse gene expression patterns between asthma tissues and multiple cancer types, indicating functional opposition at the transcriptional level. Pathway enrichment using Ingenuity Pathway Analysis identified Th1/Th2 immune axis regulation and glucocorticoid receptor signaling as central networks driving this biological divergence. Specifically, genes upregulated in asthma that elevate Th2-dominant IgE-mediated immune responses were linked to enhanced immunosurveillance and T-cell cytotoxic activation in cancer contexts, suggesting a mechanistic basis for reduced tumor initiation and progression. Meanwhile, glucocorticoid receptor isoform regulation emerged as a potential modulator linking asthma treatment to cancer vulnerability. Together, these results provide the first integrated genetic, transcriptomic, and pathway-level evidence supporting a causal immunologic framework for the inverse asthma-cancer association. This work highlights new molecular targets at the interface of allergic inflammation and tumor immunity and suggests opportunities for therapeutic repurposing of immune-modulating strategies used in asthma to inform cancer prevention and treatment. Citation Format: Kinsey Garofalo, Yinqiao Wang, Peyton Cook, Yujuan Guo, Yong Zhu. Genetic and immune signaling divergence underlies the inverse associationbetween asthma and cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3590.
Garofalo et al. (Fri,) studied this question.