Multi-omics integration reveals pan-cancer roles of ZIC family genes in prognosis, immune microenvironment remodeling, and therapeutic vulnerability

The ZIC gene family (ZIC1–ZIC5) encodes zinc-finger transcription factors with established roles in neural development. However, a systematic pan-cancer analysis integrating their multi-omics landscapes, clinical prognostic value, and immunomodulatory mechanisms remains unexplored, limiting their potential as cross-cancer biomarkers. We performed a comprehensive multi-omics analysis across 33 cancer types, assessing ZIC1-ZIC5 gene expression, prognostic significance, genomic alterations (somatic mutations, copy number variations), and immune interactions (immune infiltration, checkpoint genes, microsatellite instability, and tumor mutation burden). Drug sensitivity analysis (validated by CCK-8 assays) and immunotherapy cohort validation were conducted, with focused immune infiltration assessment in liver hepatocellular carcinoma (LIHC). Additionally, using qRT-PCR and Western blot, we assessed the expression of ZIC2 in tissues from hepatocellular carcinoma patients and investigated the transcriptional networks of ZIC genes across various cell populations within the tumor microenvironment. ZIC genes exhibited cancer-type-specific dysregulation, significantly correlating with patient survival, genomic instability, and immune cell infiltration. Drug response analysis identified ZIC expression as a potential predictive biomarker, further corroborated by CCK-8 results confirming the therapeutic vulnerability of ZIC2-high HCC cells to alisertib. Notably, distinct ZIC signatures were linked to immunotherapy outcomes, as supported by GSEA-enriched immune pathways. In LIHC, ZIC alterations were closely associated with immune microenvironment dynamics, corroborated by protein-level validation. This study identified ZIC family genes as multi-functional regulators in pan-cancer contexts, serving as promising prognostic biomarkers and therapeutic targets across cancers, particularly in LIHC. Their immune-modulatory functions highlight their potential utility in immunotherapy optimization, providing a foundation for future translational research in precision oncology.