Preclinical evidence for cytokine-based immunotherapy in pancreatic cancer treatment: A systematic review.

Pancreatic cancer remains one of the most lethal malignancies, characterized by a highly immunosuppressive tumor microenvironment (TME) and a dense desmoplastic stroma, representing a significant challenge to immunotherapy application. This systematic review evaluates cytokine-based immunotherapy as a strategy to overcome these barriers. Following PRISMA guidelines, we searched PubMed, SCOPUS, and Web of Science for original preclinical studies published between 2020 and 2025 that evaluated the administration or inhibition of cytokines in monotherapy or combined therapy with checkpoint inhibitors and chemotherapy. Risk of bias was assessed with the QUIN (in vitro) and SYRCLE (in vivo) tools. A total of 46 studies were included, revealing two primary therapeutic approaches: blocking chronic immunosuppressive factors and administering immunostimulatory cytokines. Targeting cytokines such as TGF-β and IL-6 induced high stromal remodeling and fibrosis reduction, thereby facilitating effector cell infiltration. Conversely, the delivery of pro-inflammatory cytokines (e.g. IL-2, IL-12 or IL-15) demonstrated significant potential in enhancing T-cell persistence and preventing exhaustion. Cytokine modulation was rarely sufficient as a monotherapy but produced robust antitumor responses when combined with chemotherapy or immune checkpoint inhibitors (anti-PD-1). Evidence was limited by the predominant use of subcutaneous and xenograft models that incompletely reproduce the human pancreatic stroma and by an unclear-to-high risk of bias among in vivo studies. In conclusion, manipulating the cytokine environment can convert the "cold" pancreatic tumor microenvironment into a "hot" state. Although integrating these strategies into multimodal regimens shows promise, rigorous clinical validation is essential to determine their true efficacy and safety in humans.