Integrative immunogenomic profiling identifies CALU as a brown adipocyte–linked modulator of progression and treatment response in pancreatic cancer

OBGECTIVE: Pancreatic Ductal Adenocarcinoma (PDAC) remains a lethal malignancy with limited therapeutic options. This study aimed to identify brown adipocyte-related genes (BARGs) influencing PDAC prognosis and explore their roles in the tumor microenvironment (TME) and immunotherapy response. METHODS: Transcriptomic and proteomic data from TCGA, GEO, ICGC, and CPTAC databases were analyzed to screen prognostic BARGs. Immune infiltration, immunotherapy prediction (via TIDE, IRnet, and TCIA), and drug sensitivity analyses were conducted. Single-cell RNA sequencing (CRA001160 dataset) and experimental validation (qPCR in pancreatic cancer cell lines) were performed to validate findings. RESULTS: CALU emerged as a core prognostic gene, significantly overexpressed in PDAC tissues and correlated with advanced tumor grade. High CALU expression was linked to stromal cell activation (e.g., cancer-associated fibroblasts, M1 macrophages) and suppressed T-cell infiltration, indicating immunosuppressive TME remodeling. CALU predicted resistance to CTLA4 inhibitors but showed no significant association with PD1 blockade. Drug sensitivity analysis revealed correlations between CALU and chemotherapeutic agents (e.g., TAK-715, LGK974). Single-cell analysis localized CALU to malignant and stromal cells, highlighting its role in PERIOSTIN-mediated fibroblast-malignant cell communication. Experimental validation confirmed elevated CALU expression in pancreatic cancer cell lines compared to normal cells. CONCLUSION: CALU is a critical regulator of PDAC progression, influencing stromal-TME interactions and immune evasion. It serves as a potential prognostic biomarker and therapeutic target, offering insights into combination strategies targeting stromal-immune crosstalk in PDAC.