Evaluating CD40 Agonist Alone and in Combination with IL-1R1 Blockade in Pancreatic Cancer

To investigate the immunomodulatory effects of IL-1R1 blockade in pancreatic ductal adenocarcinoma (PDAC), we performed bulk RNA sequencing of tumors subjected to distinct treatment regimens. Tumors were treated with either an anti–IL-1R1 antibody or left untreated, and another cohort received combination therapy with agonistic CD40 and anti–IL-1R1 antibodies versus CD40 agonist monotherapy. Gene ontology enrichment analysis of differentially expressed genes (p ≤ 0.05) revealed that anti–IL-1R1 treatment upregulated genes involved in RNA processing, including spliceosome-associated pathways, compared with untreated controls. Conversely, immune-related pathways—such as response to type II interferon, leukocyte-mediated immunity, and T-cell activation—were significantly downregulated in the anti–IL-1R1 group. In contrast, tumors receiving combination therapy exhibited enhanced innate and adaptive immune signatures compared to CD40 monotherapy, including antigen presentation, lymphocyte-mediated immunity, and regulation of immune effector functions. Metabolic pathways were notably downregulated in the combination group. Gene set enrichment analysis further confirmed the upregulation of key immune pathways, including NOD-like receptor signaling, NF-κB signaling, NK cell–mediated cytotoxicity, and JAK-STAT signaling, in the combination therapy group. These findings highlight the context-dependent effects of IL-1R1 blockade and support its synergistic potential with CD40 agonism in modulating the PDAC tumor microenvironment.