Targeting cytokines: Reshaping the pancreatic tumor microenvironment

Pancreatic ductal adenocarcinoma (PDAC) contains various cell types scattered by desmoplastic stroma and
communicate through small molecular weight signaling molecules called cytokines. Cytokines include in-
terleukins, chemokines, interferons, tumor necrosis, and growth factors (TGF-β, VEGF, and EGF) promote cancer
cell proliferation, differentiation, modulation of tumor microenvironment (TME), and metastasis. Targeting
cytokines/ cytokine receptor is a potential approach for modulating immune responses, increasing therapeutic
efficacy, and overcoming therapy resistance. This review summarizes the current understanding of cytokines,
their role in PDAC, and their role in combination therapies with immune checkpoint inhibitors (ICIs) and con-
ventional chemotherapies. The dual role of cytokines as immunosuppressors and immune enhancers in PDAC is
reviewed. Novel developments in combination therapies with several cytokines are summarized in terms of its
impact on PDAC growth, metastasis, and TME. The review also focuses on the ongoing translational research and
clinical trials that are essential in evolving our understanding and use of cytokines as mono or combinatorial
agents to treat PDAC.