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 interleukins, 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 conventional 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.