UCP2 Identifies Immunosuppressive Tumor-Associated Macrophages and Is Associated with Predicted Immunotherapy Resistance in Glioma

Uncoupling protein 2 (UCP2) has been extensively studied as a metabolic regulator in glioma; however, its relationship with the tumour immune microenvironment and the cellular source of its expression within the glioma tumour microenvironment (TME) remains poorly understood. This study aimed to characterise UCP2 expression at single-cell resolution and evaluate its immunological significance in glioma.

This study employed an integrative multi-omics approach incorporating bulk transcriptomics, scRNA-seq (GSE70630, GSE84465, and GSE89567; n = 13,216 cells), immune deconvolution, immunohistochemistry (n = 96 glioma patients), and immunofluorescence co-staining (n = 6).

Pan-cancer analysis confirmed UCP2 overexpression in glioma. Single-cell analysis revealed UCP2 expression within the TME is predominantly enriched in macrophage/microglial populations rather than tumour cells, reframing UCP2 as a tumour-associated macrophage (TAM)-intrinsic regulator. In the TCGA cohort (n = 670), UCP2-high tumours exhibited an immunosuppressive landscape enriched with M2 macrophages and regulatory T cells, with elevated ESTIMATE scores. UCP2 correlated strongly with HAVCR2/TIM-3 (ρ = 0.847) and lactate metabolism genes, supporting a UCP2–lactate–TAM polarisation axis. TIDE analysis predicted that UCP2-high tumours may be associated with immunotherapy resistance. Multivariate Cox regression confirmed UCP2 as an independent prognostic factor (HR = 1.294, 95% CI: 1.116–1.502, p = 6.66 × 10⁻⁴). UCP2 protein expression negatively correlated with Ki67 (ρ = −0.446, p = 5.23 × 10⁻⁶), and immunofluorescence co-staining (n = 6) confirmed co-localisation with CD68-positive TAMs.

UCP2 functions as a TAM-intrinsic immune regulator and candidate biomarker for immunosuppressive TME characterisation and immunotherapy response stratification in glioma.