Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent type of pancreatic neoplasm, accounting for more than 90 % of pancreatic cancer cases (Sarantis, Koustas, Papadimitropoulou, Papavassiliou, & Karamouzis, 2020). PDAC is an extremely aggressive malignancy, characterized by difficult and late diagnosis, as well as very low response to treatment, making it one of the most lethal cancers with the poorest prognosis. PDAC is currently the fourth leading cause of cancer-related deaths worldwide, and it could become the second by 2030 if no significant therapeutic advances are made and incidence continues to grow at the current rate (Rahib et al., 2014). Even with the few therapeutic advances achieved against PDAC, the 5-year survival rate remains as low as 9 % (Rawla, Sunkara, & Gaduputi, 2019), and most patients experience relapse in less than a year after resection (den Broeck et al., 2009).

PDAC is characterized by a highly desmoplastic microenvironment, where dense and fibrotic stroma is formed, filled with extracellular matrix proteins, growth factors, pancreatic stellate cells, cancer-associated fibroblasts, and matrix-degrading enzymes (Mascharak et al., 2023). This structural feature significantly hinders treatments for PDAC, including chemotherapy, radiotherapy, and immunotherapy, by creating a physical barrier that prevents therapeutic agents from effectively penetrating the tumor (Mascharak et al., 2023). Compared to other solid tumors, PDAC’s stromal component can occupy up to 80 % of the tumor volume (Kane et al., 2020). Moreover, the PDAC microenvironment is not only desmoplastic but also profoundly immunosuppressive. It is characterized by a deficiency of cytotoxic T lymphocytes (CTLs) and an abundance of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), type-2 immunosuppressive macrophages (M2), and tumor-associated macrophages (TAMs) (Ino et al., 2013, Kurahara et al., 2011). These immunosuppressive cells release Th2-type cytokines such as interleukin-1, interleukin-6, and interleukin-10 (IL-1, IL-6, IL-10), as well as transforming growth factor beta (TGF-β), while also expressing immune checkpoint regulators like programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4). The Th2-type cytokines and immune checkpoints help sustain the malignant phenotype by suppressing the anti-tumor activities of CD4+ and CD8+ T cells, facilitating the conversion of M1 macrophages to M2, and promoting the differentiation of myeloid cells into MDSCs (Huber et al., 2020). Additionally, cancer cells and fibroblasts secrete factors such as TGF-β and IL-10, which further enhance the immunosuppressive and fibrotic nature of the tumor and drive differentiation of immunostimulatory macrophages toward an immunosuppressive phenotype (Lefler et al., 2022, Ringuette Goulet et al., 2018, Thomas and Massagué, 2005, Tjomsland et al., 2011). Overall, the complex and hostile microenvironment of PDAC presents a significant challenge to treatment, generating a need for novel therapeutic approaches that can effectively overcome these barriers.

Current therapies for PDAC include surgical resection, which is considered the only potentially curative treatment, despite its associated risks and complications. It is also one of the most complex types of surgeries. Furthermore, only about 15–20 % of patients are eligible for surgery due to the advanced stage of PDAC at the time of diagnosis (Timmer et al., 2021). Modern radiotherapy has been explored for PDAC using regimens with higher doses and reduced toxicity to surrounding tissues, like the intestines, but significant improvements in patient survival are still being evaluated (Abrams et al., 2012). Since the majority of patients are diagnosed with advanced or metastatic disease, making them ineligible for surgery, chemotherapy remains the primary treatment option. Gemcitabine combined with Nab-Paclitaxel is the standard of care, and more recently, FOLFIRINOX (leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, and oxaliplatin) has been incorporated into the treatment regimen, showing better outcomes compared to gemcitabine alone, although with more pronounced side effects (Conroy et al., 2011, Conroy et al., 2018, Hoff et al., 2013). Despite advancements in surgical techniques, radiotherapy, and chemotherapy, the prognosis for PDAC remains poor, highlighting the urgent need for more effective therapeutic strategies.

The potential for managing PDAC lies in immunotherapy, which offers a promising approach targeting various immune checkpoints and cellular pathways. Notable strategies include checkpoint blockade inhibitors such as anti-PD-1, anti-programmed death receptor ligand-1 (PD-L1), and anti-CTLA-4. Other approaches encompass adoptive T-cell transfer using chimeric antigen receptor T cells (CAR-T), vaccines, monoclonal antibodies, and cytokine therapies. While anti-PD-1/PD-L1 therapy has shown promising results in treating other solid malignancies, outcomes for PDAC patients have been less encouraging. Numerous clinical trials have assessed anti-PD-1/PD-L1 therapy as monotherapy and in combination with other treatments (12–14, and reviewed in (Liu et al., 2022)). Until now, the most notable results were achieved in combination with gemcitabine/Nab-Paclitaxel, which demonstrated a median progression-free survival (mPFS) of 9.1 months and a median overall survival (mOS) of 15 months, compared to 8.5 months mPFS and 11.1 months mOS with gemcitabine/Nab-Paclitaxel alone or the FOLFIRINOX regimen (Conroy et al., 2011, Von Hoff et al., 2013, Weiss et al., 2018).

Other combination therapies, such as chemotherapy with anti-PD-1 and anti-C-X-C chemokine receptor type 4 (CXCR-4) inhibitors, have shown improved efficacy, resulting in a median overall survival of 7.8 months (Bockorny et al., 2020). Furthermore, checkpoint inhibitors like anti-CTLA-4, anti-TIGIT, and anti-LAG3 have undergone preclinical and clinical evaluation, both as monotherapies and in combination with chemotherapeutic agents, though enhancements in overall survival remain modest or inconclusive (Cebada et al., 2020, Ko et al., 2023, Sd et al., 2020). Additional trials involving major histocompatibility complex II (MHC-II) and CD40 agonists combined with chemotherapy and anti-PD-1 have yielded a median overall survival of up to 12.7 months, alongside evidence of immune system activation, such as increased levels of inflammatory cytokines (O’Hara et al., 2021, Wang-Gillam et al., 2013). Although these outcomes did not surpass those achieved with gemcitabine/Nab-Paclitaxel, they suggest that immune-stimulatory therapies may help reprogram the PDAC immune microenvironment, promoting more effective anti-tumor immune responses.

Cytokines mediate critical interactions between immune and tumor cells in the TME. Certain cytokines, such as IL-33, IL-4, IL-6, and IL-11, play particularly significant roles in cancer development and progression. These cytokines can attract immunosuppressive cells, fostering a more tumorigenic niche, driving tumorigenesis, and promoting inflammation-induced carcinogenesis. They can also help polarize immune cells toward immunosuppressive phenotypes (Briukhovetska et al., 2021). Conversely, many other cytokines exhibit antitumor properties and support the initiation and maintenance of anti-tumor immune responses. Notably, most cytokines are pleiotropic, meaning they can simultaneously support cancer growth and contribute to effective anti-tumor immune responses (Briukhovetska et al., 2021). These dual properties of interleukins can be leveraged to enhance immunotherapy efficacy and minimize side effects. Immune-stimulatory cytokines, such as IL-2 and IL-15, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon gamma (IFN-γ), have been used as supplemental components in broader immunotherapy approaches against PDAC (Le et al., 2019, Palmer et al., 2020, S et al., 2011, Tsujikawa et al., 2020, Wu et al., 2020). Early studies of solitary cytokine therapy showed initial success in PDAC, particularly when used in the perioperative phase (Caprotti et al., 2008, Lygidakis et al., 1998). However, several more extensive and conclusive preclinical and clinical studies have been conducted in recent years, often using cytokine therapy in combination with other immunotherapies. This chapter summarizes the most recent and significant preclinical and clinical studies using cytokine therapy against PDAC, along with their results and the potential impact on patient survival. For a more comprehensive review of cytokine therapeutics and signal transduction, we refer the reader to the following article (Leonard & Lin, 2023).