Interleukin-1 receptor type 1 in pancreatic cancer progression and metastasis: a review

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a global lethal malignancy, with increasing incidence and dismal survival rates. Inflammation plays a central role in shaping PDAC biology, and interleukin-1 receptor type 1 (IL-1R1) is a key mediator linking oncogenic signaling, stromal activation, and immune suppression. This review summarizes current insights into IL-1R1 signaling in PDAC, focusing on its role in tumor microenvironment remodeling, tumor progression, and metastasis. IL-1R1 activation by IL-1α or IL-1β triggers MyD88-dependent pathways, including NF-κB, MAPK, and STAT3, which induce pro-inflammatory cytokines, angiogenic factors, and immune checkpoints. These events contribute to the desmoplastic and immunosuppressive tumor microenvironment characteristic of PDAC. IL-1R1 orchestrates crosstalk between cancer cells, cancer-associated fibroblasts, and tumor-associated macrophages, promoting epithelial-mesenchymal transition, extracellular matrix remodeling, and immune evasion. Moreover, IL-1R1 promotes metastatic dissemination by enhancing the survival of circulating tumor cells through platelet shielding and neutrophil extracellular traps, while fostering angiogenesis and lymphangiogenesis to establish niches in the liver and peritoneum. Clinically, high IL-1R1 expression correlates with advanced disease, metastasis, and poor prognosis. Therapeutic blockade of the IL-1 pathway with agents, such as anakinra, canakinumab, or rilonacept, reduces tumor growth, metastasis, and immune suppression in preclinical PDAC models. Combination strategies with chemotherapy, radiotherapy, or immune checkpoint inhibitors further enhance anti-tumor efficacy. However, major challenges remain, including limited clinical trial data, infection risk, and the absence of predictive biomarkers. Summarily, IL-1R1 is a central driver of PDAC aggressiveness and a therapeutic target. Targeting this pathway may enable biomarker-guided strategies to improve outcomes in this disease.

Keywords: Epithelial–mesenchymal transition; IL-1 receptor type 1; Immunotherapy resistance; Pancreatic ductal adenocarcinoma; Tumor microenvironment; Tumor-associated macrophages.