Integrative Multi-Omic Profiling of the Human Phosphatome Identifies DUSP15 as a Tumour-Selective Regulator of Immune-Metabolic Reprogramming in Chromophobe Renal Cell Carcinoma

Protein phosphatases constitute a critical superfamily of signalling enzymes, yet their tissue- and tumour-specific roles remain incompletely defined. Chromophobe renal cell carcinoma (KICH) is a rare and poorly understood kidney malignancy that lacks validated biomarkers or therapeutic targets. To address this gap, a phosphatase-wide, multi-omic integration of The Cancer Genome Atlas (TCGA), supported by validation across ten independent GEO microarray cohorts, systematically charted the human phosphatome across cancers. This analysis pinpointed the dual-specificity phosphatase DUSP15 as the most KICH-selective phosphatase (Tau = 0.977), showing near-exclusive expression and outstanding discriminatory performance (AUC = 0.975; OR = 4.83; p = 6.2e-7). Transcriptome-wide correlation and enrichment analyses revealed that DUSP15 expression is associated with activation of oxidative phosphorylation, MYC targets, and DNA repair, together with suppression of interferon and inflammatory signalling. Immune deconvolution confirmed reduced infiltration of regulatory T cells, dendritic cells, and overall immune content, consistent with an immune-desert phenotype. Single-cell RNA-seq further localised DUSP15 expression to a rare regenerative epithelial population enriched for acid-base transport genes. Collectively, these findings identify DUSP15 as a tumour-selective phosphatase that shapes immune-metabolic tumour programming in KICH, underscoring the utility of integrative multi-omics for revealing novel biomarkers and regulatory axes in rare cancers.