Pancreatic ductal adenocarcinoma (PDAC), as the most frequent form of pancreatic malignancy, still is associated with a dismal prognosis. Due to its late detection, most patients are ineligible for surgery, and chemotherapeutic options are limited. Tumor heterogeneity and a characteristic structure with crosstalk between the cancer/malignant cells and an abundant tumor microenvironment (TME) make PDAC a very challenging puzzle to solve. Thus far, targeted therapies have failed to substantially improve the overall survival of PDAC patients. Immune checkpoint inhibition, as an emerging therapeutic option in cancer treatment, shows promising results in different solid tumor types and hematological malignancies. However, PDAC does not respond well to immune checkpoint inhibitors anti-programmed cell death protein 1 (PD-1) or anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) alone or in combination. PDAC with its immune-privileged nature, starting from the early pre-neoplastic state, appears to escape from the antitumor immune response unlike other neoplastic entities. Different mechanisms how cancer cells achieve immune-privileged status have been hypothesized. Among them are decreased antigenicity and impaired immunogenicity via both cancer cell-intrinsic mechanisms and an augmented immunosuppressive TME. Here, we seek to shed light on the recent advances in both bench and bedside investigation of immunotherapeutic options for PDAC. Furthermore, we aim to compile recent data about how PDAC adopts immune escape mechanisms, and how these mechanisms might be exploited therapeutically in combination with immune checkpoint inhibitors, such as PD-1 or CTLA-4 antibodies.

Regulation of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/Rel transcription factors (TFs) is extremely cell-type-specific owing to their ability to act disparately in the context of cellular homeostasis driven by cellular fate and the microenvironment. This is also valid for tumor cells in which every single component shows heterogenic effects. Whereas many studies highlighted a per se oncogenic function for NF-κB/Rel TFs across cancers, recent advances in the field revealed their additional tumor-suppressive nature. Specifically, pancreatic ductal adenocarcinoma (PDAC), as one of the deadliest malignant diseases, shows aberrant canonical-noncanonical NF-κB signaling activity. Although decades of work suggest a prominent oncogenic activity of NF-κB signaling in PDAC, emerging evidence points to the opposite including anti-tumor effects. Considering the dual nature of NF-κB signaling and how it is closely linked to many other cancer related signaling pathways, it is essential to dissect the roles of individual Rel TFs in pancreatic carcinogenesis and tumor persistency and progression. Here, we discuss recent knowledge highlighting the role of Rel TFs RelA, RelB, and c-Rel in PDAC development and maintenance. Next to providing rationales for therapeutically harnessing Rel TF function in PDAC, we compile strategies currently in (pre-)clinical evaluation.

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with limited treatment options and a high recurrence rate. Recurrence often occurs with metastasis, for which cancer cells must adapt to isolation stress to successfully colonize distant organs. While the fibronectin–integrin axis has been implicated in this adaptation, its regulatory mechanisms require further elaboration. Methods: We utilized genetically engineered PDAC mouse models with c-Rel knockout, overexpression and fibronectin (FN1) depletion, alongside in vitro assays, to assess EMP, extracellular matrix (ECM) remodeling, and resistance to anchorage-independent growth. Functional analyses, including transcriptomics, Cut&Run, flow cytometry, immunohistochemistry, and metastatic assays, were performed to elucidate the role of c-Rel in fibronectin–integrin signaling during PDAC progression. Results: We identified c-Rel as an oncogenic driver in PDAC that promotes EMP, ECM remodeling, and survival under isolation stress. c-Rel directly regulates FN1 and CD61/integrin β3 (ITGB3) transcription, enhancing cellular adaptability in metastatic settings. While FN1 is dispensable for EMT, its absence significantly impairs metastatic colonization and anchorage-independent growth. Conclusions: Our findings suggest that c-Rel can regulate PDAC progression and metastasis by modulating the tumor microenvironment and stress resistance. Targeting the c-Rel–fibronectin–integrin axis may offer novel therapeutic strategies to mitigate disease progression.