While precision oncology requires robust biomarkers, current predictors for lung adenocarcinoma (LUAD) often show limited clinical utility. This study investigates the multifaceted roles of ZC3H12D, a novel immunomodulatory molecule, in LUAD progression and tumor microenvironment regulation. Multi-omics analyses integrated ZC3H12D transcriptomic (511 tumors vs 59 normals), proteomic (74 tumors vs 69 normals), and single-cell RNA-seq data (15 tumors vs 11 normals). Immunohistochemistry validated ZC3H12D expression in 51 matched pairs. Computational biology approaches assessed immune infiltration, genomic instability (TMB/MSI/HRD), and pathway enrichment. Functional validation employed ZC3H12D knockdown in PC9 cells with colony formation and transwell assays. Multi-omics verification confirmed ZC3H12D upregulation in LUAD at both mRNA and protein levels (p < 0.001), with single-cell resolution revealing predominant localization in tumor-infiltrating immune cells. Moreover, ZC3H12D expression positively correlated with immune regulatory genes while inversely associating with genes involved in cellular respiration. Its expression was also linked to clinical markers such as TMB, MSI, HRD, tumor purity, and ploidy. Notably, high ZC3H12D expression revealed Immune-infiltrated microenvironment and favorable prognosis, despite silencing ZC3H12D resulted in significant inhibition of tumor cell proliferation and invasion in vitro (p < 0.001). Our findings demonstrate that high ZC3H12D expression in immune cells appears to enhance antitumor immune activity, whereas lower expression in malignant cells contributes to reduced cellular proliferation and migration. This spatial duality challenges conventional biomarker paradigms and provides mechanistic insights for developing cell type-targeted therapies.
© 2025. The Author(s).