Abstract
Background: Cutaneous melanoma (SKCM) presents significant therapeutic challenges due to heterogeneity and acquired resistance to targeted and immune checkpoint blockade therapies. IQCE, a ciliary scaffold protein, has poorly defined roles in cancer. Its clinical significance, molecular mechanisms, and impact on the tumor microenvironment (TME) and therapy response are largely unknown. Methods: We conducted a comprehensive pan-cancer multi-omics analysis of IQCE using genomic, transcriptomic, proteomic, spatial transcriptomic, single-cell transcriptomic, and pharmacogenomic datasets. Analyses included differential expression, survival, pathway enrichment, immune deconvolution, cellular localization, and drug sensitivity prediction. Results: IQCE was significantly upregulated in multiple solid tumors, most notably cutaneous melanoma (SKCM), liver hepatocellular carcinoma (LIHC), and glioblastoma (GBM), demonstrating strong diagnostic value. High IQCE independently predicted poor prognosis in SKCM. Mechanistically, elevated IQCE correlated with suppression of immune pathways (e.g., cytokine signaling), inhibition of apoptosis, and activation of RAS/MAPK/RTK oncogenic signaling. Single-cell and spatial analyses confirmed IQCE enrichment specifically within malignant cells. High IQCE was associated with broad chemoresistance. Pharmacogenomic profiling revealed a consistent inverse correlation between IQCE expression and sensitivity to the p53-reactivating compound RITA. Conclusion: IQCE emerges as a novel oncogene-associated biomarker with significant diagnostic and prognostic utility, particularly in SKCM. It promotes an immunosuppressive TME and oncogenic signaling while being localized to malignant cells. Although associated with chemoresistance, the vulnerability of IQCE-high tumors to RITA offers a promising therapeutic strategy. IQCE represents a compelling target for precision oncology.