Multi-omics data mining reveals macrophage-mediated effects of cathepsin B on esophageal adenocarcinoma risk

Esophageal adenocarcinoma (EAC), a predominant esophageal cancer subtype, has risen markedly in Western populations, yet its pathogenesis remains poorly defined. Cathepsins, a family of lysosomal proteolytic enzymes, have been implicated in the progression of various tumors. However, the causal relationship between the cathepsin family and EAC remains unresolved. In order to explore the association between EAC and cathepsin family, and the potential pathogenesis of EAC, we designed this research. Using an integrative multi-omics approach including Mendelian randomization (MR), transcriptome-wide association study (TWAS), single-cell RNA sequencing (scRNA-seq), and single-cell expression quantitative trait locus (sc-eQTL) analyses, we investigated how cathepsin B (CTSB) influences EAC risk. MR and TWAS revealed reduced CTSB expression correlated with higher EAC risk, validated experimentally via immunohistochemistry. scRNA-seq localized CTSB predominantly in tumor-infiltrating macrophages and highlighted its role in modulating intercellular signaling. Macrophage-specific sc-eQTL colocalization analyses identified shared causal variants linking CTSB to macrophage infiltration. MR and protein docking confirmed direct interaction between CTSB and macrophage scavenger receptor (MSR), suggesting CTSB shapes macrophage phenotypes that drive EAC risk. Our findings establish CTSB's causal role in EAC via MSR regulation, proposing CTSB-targeted modulation of tumor-associated macrophages as an effective therapeutic strategy.