Pancreatic ductal adenocarcinoma (PDAC) remains one of the solid cancers with the worst prognosis. It has become the third leading cause of cancer-related death, largely because of late discovery and unresectability but also because of the lack of highly efficient chemo-, immuno-, and radiotherapies [1]. The ESPAC (European Study Group for Pancreatic Cancer) trials [2-5] showed that chemotherapy improves survival in the adjuvant and neoadjuvant setting in borderline resectable patients. Still, survival remains worse than in most other cancers. While immunotherapy has been a game changer in many cancers, there has not been such a breakthrough for pancreatic cancer so far [6].

An overall survival of 10% at 5 years has not been exceeded in most countries [7]. In Switzerland, overall survival has recently increased to 13% for the period, whereas incidence also increased by more than 10% compared with the period of 2008‐2012 [8].

Given that chemotherapy administration is frequently constrained by rapid patient deterioration, including weight loss and impaired glucose metabolism, we aim to investigate the association between these clinical features and the tumor stage/prognosis with the inflammatory interleukin 6 (IL-6)/glycoprotein 130 (GP130)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway.

The proinflammatory cytokine IL-6 plays a pivotal role in tumorigenesis by activating the JAK-STAT3 signaling cascade. Upon binding to its IL-6 receptor α (IL-6Rα) on the cell surface, IL-6 induces dimerization with the coreceptor GP130, leading to phosphorylation of JAKs and subsequent activation of STAT3. Phosphorylated STAT3 translocates to the nucleus, where it promotes the transcription of genes involved in cell survival and proliferation. Recent findings have identified integrin β3 as a gene product associated with prognosis [9]. Moreover, IL-6/STAT3 signaling has been implicated in the progression from pancreatic intraepithelial neoplasia to PDAC [10]. IL-6 also contributes to the activation of cancer-associated fibroblasts via pancreatic stellate cells, key components of the tumor stroma [11]. Additionally, PDAC cells appear to exploit IL-6 signaling to prime the liver microenvironment for metastatic colonization [10]. These insights suggest that targeting the IL-6/GP130/JAK/STAT3 axis may offer a promising therapeutic strategy for pancreatic cancer. A phase 1 clinical trial has been initiated [12], evaluating a combination therapy comprising trametinib (mitogen-activated extracellular signal-regulated kinase [MEK] inhibitor), ruxolitinib (JAK2/STAT3 inhibitor), and retifanlimab (programmed cell death protein 1 [PD-1] inhibitor) [13-15]. Figure 1 shows the relevance of the pathway.

Pancreatic cancer is increasingly recognized for its impact on glycemic metabolism, with inflammatory cross talk proposed as a key underlying mechanism. Tumor-derived cytokines, notably IL-6 and tumor necrosis factor α (TNF-α), contribute to adipose tissue inflammation, impairing insulin sensitivity. TNF-α interferes with insulin receptor signaling in adipocytes, potentially promoting lipolysis and elevating levels of nonesterified fatty acids [16], which are commonly observed in obesity and type 2 diabetes, and are known to exacerbate insulin resistance and induce β-cell toxicity [17]. A study by Fogar et al [18] demonstrated a correlation between portal vein IL-6 levels and fasting serum glucose concentrations. Furthermore, preclinical evidence indicates that IL-6/GP130/JAK/STAT3 pathway activation upregulates autotaxin expression in adipocytes, while genetic suppression of autotaxin enhances insulin sensitivity and reduces hepatic steatosis in knockout mice compared to wild-type controls [19].

Inflammatory signaling within the tumor stroma is also implicated in chemotherapy resistance and disease progression. Specifically, the IL-6/GP130/JAK/STAT3 axis has been associated with cancer cachexia [20] and neural invasion [21]. Several therapeutic agents targeting this pathway have been proposed for pancreatic cancer treatment [22]. Given the marked heterogeneity of pancreatic tumors, precision therapies are urgently needed. However, the prevalence and clinical relevance of IL-6/GP130/JAK/STAT3 pathway activation in patients with pancreatic cancer remain poorly defined. Moreover, it is unclear whether pathway activation correlates with metabolic dysregulation or the presence of cachexia [23].

This study aims to evaluate the activation of the IL-6/GP130/JAK/STAT3 signaling pathway in previously collected tissue samples—including pancreatic biopsies, surgical specimens, and liver biopsies—from patients diagnosed with pancreatic adenocarcinoma. The study will quantify pathway activation and assess its association with tumor stage, overall survival, and metabolic parameters, including the requirement for oral antidiabetic agents, insulin therapy, and hemoglobin A_1c levels.

This project was reviewed and approved by the Ethics Committee of Bern, Switzerland (project 2024‐01215).

This project is expected to enhance our understanding of the role of IL-6/GP130/JAK/STAT3 pathway activation and its histological patterns in shaping the clinical phenotype of pancreatic adenocarcinoma, particularly its impact on glucose metabolism. These insights may contribute to the development of more targeted therapeutic strategies and help identify patient subgroups that could benefit from an IL-6 receptor blockade as part of their treatment regimen.

There is no risk to individual patients, as the study relies exclusively on previously collected routine clinical data and archived biopsy material. All data will be pseudonymized before analysis, and study results will not influence patient care.

The risk of inadvertent patient identification is minimal. Access to uncoded data is restricted to trained medical personnel—specifically, the three named investigators at HFR and the pathologist at Promed—who are bound by professional confidentiality through both their employment and the research framework. All digital files will be password protected, and physical documents will be stored securely in restricted-access facilities. This project is fully compliant with Swiss legal and ethical standards.

To minimize the risk of biased conclusions due to nonrepresentative sampling, we will include all patients diagnosed with pancreatic cancer at HFR, applying the least restrictive exclusion criteria possible. As HFR is the only hospital in the canton of Fribourg with an oncology department, the vast majority of patients with pancreatic cancer in the region receive care at this institution. Consequently, only a small number of patients who seek treatment outside the canton are expected to be excluded, supporting the representativeness of our sample.

We hypothesize that IL-6/GP130/JAK/STAT3 pathway activation is comparable between tumor tissue and adjacent stromal tissue. Furthermore, we expect that patients with stronger pathway activation will exhibit poorer prognosis, more significant weight loss, and greater or more recent disturbances in glucose metabolism. We do not anticipate an association between pathway activation and long-standing diabetes. Potential confounding factors include pancreatitis and other concurrent inflammatory conditions, such as pneumonia, which may independently influence pathway activation and metabolic parameters.

A major strength of this study is that it represents only the second investigation of IL-6/GP130/JAK/STAT3 pathway activation in a substantial number of pancreatic cancer patient samples, following the recent work by Campos et al [9]. While the Campos study focused primarily on mechanistic insights, our study emphasizes the correlation between pathway activation and clinical symptoms and outcomes, offering novel perspectives on its relevance in patient care. We will also assess the presence of pancreatitis and antibiotic use, which may help exclude infectious diseases as sources of inflammation.

A potential limitation is the sample size, which may be insufficient to detect statistically robust associations across all variables. Additionally, the study design does not allow for longitudinal analysis, as only a single tissue sample per patient is available. Therefore, we cannot determine whether pathway activation varies over the course of disease progression.

This study contributes important new insights into the IL-6/GP130/JAK/STAT3 pathway activation in patients with PDAC. Preliminary findings suggest that patients with advanced-stage disease exhibit higher levels of pathway activation in both tumor and adjacent stromal tissue. These results support the hypothesis that stromal activation mirrors tumor activation and may play a role in disease progression. To further disentangle the influence of patient or tumor genetics from disease dynamics, longitudinal sampling would be necessary to assess changes in pathway activation over time.