A prognostic 19-gene signature and LBP-mediated immune dysregulation define the tumor microenvironment in...

Kidney renal clear cell carcinoma (KIRC) exhibits pronounced immune heterogeneity, and immune dysregulation within the tumor microenvironment (TME) contributes to poor outcomes. Leveraging TCGA-KIRC RNA-seq, we stratified patients by immune-cell infiltration and immune-regulatory gene expression to define a poor-survival subgroup for discovery. Differential expression analysis prioritized lipopolysaccharide-binding protein (LBP) and generated an immune-relevant candidate set that was refined from 406 to 87 genes by stepwise logistic regression and then benchmarked through one million random 20-gene models, yielding a final 19-gene prognostic signature. Six immune-cell features associated with survival were identified, including higher M0 macrophages, regulatory T cells, activated CD4 memory T cells, plasma cells, and neutrophils (worse prognosis) and resting mast cells (better prognosis). LBP was highly expressed in the poor-survival subgroup and functionally validated in vitro: RT-PCR/ELISA/Western blot and cell-based assays showed that LBP promotes tumor-cell migration and macrophage activation, while LBP neutralization reversed these effects, supporting its role as a mediator of tumor-immune crosstalk. The 19-gene panel robustly distinguished poor-survival patients, achieving AUC = 0.84 in TCGA-KIRC and 0.79-1.00 across three external datasets. Pathway analysis implicated ERK signaling, immune suppression, and chronic inflammation. These findings establish a clinically relevant 19-gene signature and highlight LBP-driven immune dysregulation as a potential target in KIRC.