PC primarily consists of pancreatic ductal adenocarcinoma (PDAC), a highly aggressive and treatment-resistant malignancy [1]. Due to the nonspecific nature of early symptoms, PDAC is often diagnosed at advanced stages, including early metastasis or late-stage disease. The primary treatment for PDAC remains standard cytotoxic chemotherapy, which only marginally improves overall survival (OS) by a few months [2]. The development of PDAC, like other solid tumors, is driven by the inflation of specific genetic mutations, including alterations in the oncogene KRAS (e.g., the G12D mutation) [3] and the tumor suppressor gene TP53 [4]. These genetic changes are accompanied by histological transformations during the progression of the disease [5]. The morphological evolution begins with precursor lesions which gradually develop into invasive adenocarcinoma [6]. As the disease progresses, significant changes also occur in the surrounding tissue stroma. The non-cancerous stroma, which consists of components such as immune cells and connective tissue, is essential for maintaining tissue homeostasis and repairing damage. Moreover, cancer cells exploit this normal physiological response to develop a tumor microenvironment (TME) that supports their progression [7]. This phenomenon, where cancer mimics "persistent wounds," reflects changes in the stroma that result from "abnormal wound healing" processes [8]. Numerous "immune defects" have been implicated in PDAC, according to accumulated evidence. These include immune checkpoint signaling, heterogeneous thick stroma that prevents effector cell infiltration, a lack of high-quality effector cells, and an immunosuppressive TME (Figure 1). Immunotherapeutic strategies hold substantial promise in eliciting robust immune feedback against tumors [9]. Since 2010, clinical research leveraging diverse immunotherapeutic techniques has achieved notable success in treating various cancers [10]. Unlike traditional tumor-targeted therapies, immunotherapy generates immune responses specifically directed at cancer cells, which can persist long after the treatment ends [11]. However, immunotherapy has demonstrated limited capability in the majority of PDAC cases. This limitation is largely due to the TME of PDAC, which is characterized by a scarcity of effector T cells formerly disclosed to tumor antigens [12]. While immunotherapy has revolutionized the management of several solid tumors, its impact on survival outcomes in PDAC remains modest [13]. The resistance of PDAC to immunotherapy can be attributed to its unique biological features, including a low mutational burden and a TME [14]. Combining immunotherapy with chemotherapy or surgery may provide synergistic benefits. Numerous cytotoxic drugs and adjuvant therapies can enhance the effectiveness of immunotherapy by promoting immunogenic cell death, counteracting immune evasion mechanisms, and reducing immunosuppression within the TME [15]. Currently, immunotherapy is emerging as a key focus in PC treatment. PDAC employs several mechanisms to evade immune detection [16]. In the treatment and prognosis of patients with ductal PC, understanding the molecular components is becoming more and more crucial. The molecular understanding of pancreatic cancer involves a complicated interaction of multiple variables (Figure 2). With an emphasis on clinical studies conducted in the last ten years, we present here a summary of the immunotherapies that are now on the market and their anti-tumor efficacy in PC in terms of immune stimulation and survival.

PC typically develops through a stepwise progression, often originating from pancreatic intraepithelial neoplasia (PanIN). A key initiating event in most pancreatic ductal adenocarcinomas is the mutation of the Kirsten rat sarcoma (KRAS) oncogene, with approximately 95% of PanIN lesions containing KRAS mutations located on chromosome 12 [17]. Tumor suppressor genes are vital for preventing uncontrolled cell growth, and three of these are commonly mutated in pancreatic cancer. Cyclin-dependent kinase inhibitor 2A (CDKN2A) is altered in 95% of pancreatic tumors, either through mutations or promoter methylation [18]. The proteins p16/Ink4a and p14/Arf, which are encoded by CDKN2A, limit the action of Cyclin-dependent kinase 4/6 (CDK4/6) and stop the p53 tumor suppressor from being degraded by Mouse double minute 2 homolog (MDM2) [19]. Cellular proliferation is further promoted by the inactivation of the RB tumor suppressor caused by hyperactivation of CDK4/6 [20].
The tumor suppressor p53, which is mutated in 75% of pancreatic ductal adenocarcinomas (PDAC), stops working in advanced stages of the disease [21]. p53, sometimes referred to as the "guardian of the genome," typically causes cancer cells to undergo apoptosis. Mothers Against Decapentaplegic Homolog 4 (SMAD4) is another important mutation linked to the downregulation of SMAD4 protein production. Signaling from the TGF-beta family of ligands is mediated by SMAD4 and can either stimulate apoptosis or cellular growth. About 55% of pancreatic adenocarcinomas have SMAD4 mutations [22]. The progression of PC is also influenced by abnormal autocrine and paracrine signaling. Numerous mechanisms that promote invasion, and proliferation are stimulated by signaling molecules such insulin-like growth factor 1, fibroblast growth factor, and hepatocyte growth factor. The majority of clinical experiments that have attempted to target these pathways have failed.

The pancreatic TME is highly immunosuppressive and exhibits minimal immune cell infiltration [23]. The limited presence of T cells may partially result from the low mutational burden characteristic of PDAC, which leads to a scarcity of neoantigens. Neoantigens function as immune recognition markers and are crucial for inducing robust T cell responses [24]. immunological evasion and exclusion from the TME are made possible by other mechanisms that limit anti-tumor T cell invasion and encourage immunological suppression. The extracellular matrix (ECM), cancer cells, and non-cancerous cells mostly pro-tumorigenic stromal, immune, and endothelial cells make up the TME [25]. By inducing regulatory T cells (Tregs), tumor-associated macrophages (TAMs), T-helper 2 (Th2) cells, and myeloid-derived suppressor cells (MDSCs), the overabundance of these chemicals causes the immune system to shift from active surveillance to tolerance. Tumor migration, angiogenesis, and proliferation are encouraged by this changed immunological environment [26]. These immune cell populations inhibit effector CD4+ and CD8+ T cells as well as natural killer (NK) cells' ability to fight tumors. Additionally, these pro-tumorigenic cytokines prevent dendritic cells (DCs) from maturing and surviving [27]. DCs are essential for triggering efficient anti-tumor T cell feedback because they are strong antigen-presenting cells (APCs). Better survival results have been linked to PDAC patients having higher amounts of DCs in their blood and tumor tissues [28].
By downregulating elements of the antigen presentation machinery, including MHC class I, PDAC tumors further avoid immune detection [29]. Alongside this, there is a rise in the expression of inhibitory immunological checkpoint ligands and apoptotic regulatory proteins which promote apoptotic resistance [30]. By stimulating cancer-associated fibroblasts (CAFs), PDAC physically separates anti-tumor immune cells from the TME [23]. By rearranging the extracellular matrix and depositing collagen, CAFs promote fibrosis and cause a desmoplastic reaction. This physical barrier caused by the desmoplastic stroma, which can make up 50-80% of the tumor volume, hinders vascularization, prevents anti-tumor immune cells from infiltrating, and reduces the effectiveness of systemic treatments [31]. Notably, this barrier is observed in both primary and metastatic pancreatic tumors [32]. Together, these factors contribute to the immunosuppressive nature of the PDAC TME, accounting for the poor response to both chemotherapy and immunotherapy [33].

A desmoplastic reaction fueled by a heterogeneous cell population characterizes the microenvironment of pancreatic cancer. By generating metalloproteinases, which help to alter the extracellular matrix, pancreatic stellate cells contribute significantly to normal tissue remodeling. On the other hand, cytokines or other soluble substances that activate them cause fibrosis and increase intratumoral pressures, which makes it difficult to administer chemotherapy and creates an environment that is not conducive to immune cell growth [34]. Tumor development and aggressiveness are greatly influenced by these stromal components [35].
Natural nonsulfated glycosaminoglycan hyaluronan is a key component of the EM. Although hyaluronan is found in normal connective, neural, and epithelial tissues, high amounts of it in cancers have been associated with a worse prognosis, faster tumor growth, and a lower chance of survival. Pegylated hyaluronidase (PEGPH20) was used in an attempt to break down this barrier because of the high interstitial pressures inside tumors that hinder perfusion. However, there was no increase in survival outcomes for the entire study group in a phase II trial that combined gemcitabine, nab-paclitaxel, and PEGPH20 [36]. Furthermore, unexpected toxicities resulted from hyaluronan's extensive presence. The FDA issued a clinical hold on the trial following the observation of unexpected arterial and venous thrombosis. This necessitated protocol modifications, including the mandatory use of lovenox anticoagulation to mitigate life-threatening blood clot risks.
Similarly, the SWOG trial that combined FOLFIRINOX and PEGPH20 initially relied on aspirin for prophylaxis. This approach was found to be insufficient, prompting amendments to require lovenox instead. However, the trial was ultimately halted by the data and safety monitoring committee due to a lack of clinical efficacy.

Despite advancements in chemotherapy, survival rates for PC patients remain dismally low. Research has identified a subset of resistant cells that evade most therapeutic agents, contributing to tumor relapse and metastasis. Cancer stem cells (CSCs) which constitute less than 1% of the tumor cell population, are characterized by markers such as CD24, CD44, CD133, CXCR4, ESA, and nestin [37]. Maintaining CSCs, stimulating pancreatic stellate cells, and controlling the tumor stroma all depend on the hedgehog (Hh) signaling system [38]. Tumor cells reactivate the route by overproducing Hh ligands, even though it is normally inactivated after birth and mostly active during embryonic development [39]. When these ligands attach to the PTCH1 receptor, SMO is internalized and degraded, which permits the transcription factors GLI1 and GLI2 to go into the nucleus. Numerous genes, such as those encoding extracellular matrix (ECM) proteins, are driven to transcribe by this mechanism [40].
The first SMO antagonist to be discovered was cyclopamine, which had notable efficacy in preclinical studies [41]. Cyclopamine therapy in PC cell lines led to an elevation of E-cadherin and a downregulation of snail. In orthotopic models, cyclopamine efficiently decreased metastasis and shrunk primary tumors when paired with gemcitabine. In a phase II trial, gemcitabine and vismodegib, a second-generation SMO antagonist authorized for advanced basal cell carcinoma, were assessed together. The main results of this double-blind trial was progression-free survival (PFS), and 106 patients were randomly assigned. The median PFS for the combination treatment was 4 months, while the median PFS for gemcitabine alone was 2.5 months. At 6.9 and 6.1 months, respectively, the overall survival rates did not differ appreciably [42].
Unexpectedly, Saridegib (IPI-926) demonstrated worse outcomes in a phase II randomized trial, where patients receiving the combination therapy had shorter survival [43]. It was hypothesized that stromal degradation facilitated metastasis. Interestingly, a phase I trial combining Saridegib with FOLFIRINOX showed promising results, reporting a 67% response rate. However, this trial was not continued, and the development of Saridegib was ultimately discontinued [44].
The Notch signaling pathway is highly conserved and plays a key part in regulating neurogenesis during embryonic development. While the precise molecular mechanisms by which Notch contributes to PC pathogenesis remain unclear, it is known to interact with other signaling pathways such as MEK/ERK, Hedgehog (Hh), and Wnt, among others [45]. Targeting PC by inhibiting γ-secretase, an enzyme that activates Notch, is a unique treatment strategy. By blocking the epithelial-mesenchymal transition (EMT) and reducing the number of pancreatic CSCs, γ-secretase inhibitors (GSIs) have shown promise in reducing the proliferation [46]. Because tumor cells overexpress the notch ligand delta-like ligand 4 (DLL4), notch signaling is activated in CSCs [47]. By focusing on CSCs, the DLL4 inhibitor demcizumab has demonstrated promise in overcoming chemotherapy resistance [48].
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway has also been implicated in cancer progression. This pathway transmits signals from tyrosine kinase receptors and plays a role in mediating inflammation in both tumor and host tissues. In tumors with active KRAS mutations, STAT3 is especially crucial for the development of PDAC. Capecitabine and rufolitinib, a JAK1/JAK2 inhibitor that has been licensed for the treatment of high-risk myelofibrosis (MF) and hydroxyurea-intolerant/refractory polycythemia vera (PV), were studied together for pancreatic cancer. However, a phase III trial was discontinued because interim analysis revealed no discernible improvement [49].
In mice models of pancreatic cancer, STAT3 inhibition has been shown to be effective in slowing tumor growth [50]. The first-in-class cancer "stemness" inhibitor napabucasin targets the spherogenesis of CSCs and STAT3-driven gene transcription. Napapucasin demonstrated encouraging outcomes in early clinical trials. Diarrhea, nausea, vomiting, and electrolyte abnormalities were the most frequent side effects in a phase Ib/II trial with 71 participants; no unexpected toxicities were reported. According to preliminary statistics, the median overall survival was over 10.4 months, while the median PFS was over 7.1 months [51].

Just 5-10% of cases of PC are familial in origin; most occurrences are sporadic. BRCA1/2 and PALB2 are the genes most frequently linked to familial PC. BRCA2 mutations cause up to 17% of familial instances of PC and increase the risk by 3.5 times [52]. Tumor suppressor genes BRCA1 and BRCA2 are essential for DNA repair. Their protein products combine to produce a complex that is necessary for fixing double-strand breaks in DNA. The base excision repair mechanism involving poly-ADP ribose polymerases (PARP) compensates for the repair process in the presence of BRCA mutations, which makes PARP a desirable target for therapy. A phase I/II clinical trial combining gemcitabine, cisplatin, and veliparib was carried out by O'Reilly et al. Nine of the 17 patients who were enrolled in the phase 1 dose escalation study had a BRCA mutation. This tiny group had an 88% disease control rate and a remarkable 66% objective response rate. Larger studies are now being conducted to further assess this promising combination therapy, with hematologic toxicities being the primary dose-limiting adverse effects [53].
An estimated 3.9-35% of pancreatic tumors have acquired somatic mutations [54, 55]. The phase III NOVA research, which demonstrated the effectiveness of the PARP-1/2 inhibitor niraparib in treating patients with platinum-sensitive relapsed ovarian cancer, has validated this idea in the context of ovarian cancer. When compared to a placebo, the highest improvement in PFS was shown in cancers with germline BRCA mutations and in non-mutated BRCA tumors displaying homologous recombination deficiency (HRD) [56]. The HRD score is a measure of genomic instability that indicates a tumor's lack of homologous recombination DNA repair. Responses to PARP inhibitors and platinum-based chemotherapy have both been predicted using this score. Patients with refractory metastatic PC are presently being randomly assigned to FOLFIRI with or without ABT888 in the phase II trial SWOG S1513. Even though the data and safety monitoring committee recently ended this experiment, additional analyses are being carried out to assess responses according to the HRD score [57].

Monoclonal antibodies excellent specificity, adaptability, and affordability have made them the most widely used immunomodulatory strategy. The light and heavy chains of immunoglobulin contain both constant and variable sections that make up immunoglobulin G (IgG) antibodies, which are designed to target particular antigens [58]. Antibodies immunomodulatory activity depends on their capacity to attach specifically to elements of the immune recognition pathway, which either permits immune cell recognition or prevents tumor cells from evading the immune system. Monoclonal antibodies' variable domain is altered in cancer treatment to target and bind particular receptors on immune or malignant cells. This approach is highly versatile, as antibody-based therapies can be used not only for immunomodulation but also for direct cytotoxic effects [59].
However, when compared to the standard of care for patients with stage II-IV cancer undergoing palliative treatment, a meta-analysis of four randomized controlled trials assessing cetuximab, an EGFR inhibitor, in PDAC revealed no discernible clinical improvement [60]. As a result, antibody-based immunomodulation has gained more attention. A 0% response rate in PD-L1 positive cases indicates that these antibody-based immune checkpoint medications have previously had poor response rates in non-dMMR PDAC patients [61]. In order to overcome this problem, antibody treatments are frequently investigated in conjunction with chemotherapy in an effort to produce synergistic tumor damage. The goal of this combined method is to increase the possibility for therapeutic success by combining the cytotoxic effects of chemotherapy with improved immunological detection of malignant cells.
By blocking immune checkpoint pathways, these therapies can inadvertently cause the immune system to target normal cells, resulting in various autoinflammatory side effects. The most common of these include hepatitis, pneumonitis, and thyroid dysfunction [62]. Bispecific T-cell engagers are a novel approach being investigated in acute myeloid leukemia and prostate cancer to address these issues. By pushing T cells closer to the tumor cells for improved recognition, these molecules' binding sites for both T cells and tumor-specific antigens increase specificity [63]. The FDA approved the anti-CD3 x anti-delta-like ligand 3 (anti-DLL3) bispecific antibody tarlatamab for the treatment of platinum-refractory small cell lung cancer (SCLC), demonstrating the therapeutic promise of this strategy [64]. Bispecific antibodies have a bright future in the therapy of solid malignancies, according to these studies.

In order to improve the immune system's capacity to heal tissues or fight off cancer, autoimmune illnesses, and infectious diseases, cellular therapy includes a broad range of pharmacological techniques that entail the autologous or allogeneic transfer of cells into a patient [73]. Adoptive cell therapy is the term used to describe the therapeutic transfer of immune cells in the treatment of cancer [74]. These treatments' genetic alterations allow for the accurate targeting of tumor-specific responses, providing high specificity, less toxicity, fewer opportunities for tumor escape or resistance to treatment, and the potential to multiply and move through intricate TME [75]. Agents that target advanced melanoma and hematogenous cancers are among the FDA-approved cellular treatments as of February 2024. Approval will be extended to advanced synovial sarcoma by August 2024 and to extensive-stage SCLC by June 2024. Ongoing research is focused on expanding these therapies to solid tumors [76]. However, obstacles remain, such as challenges posed by the tumor microenvironment, tumor antigen heterogeneity, and the need for detailed structural knowledge of antigen-presenting cells for effective target design [77]. Further, cellular therapy holds considerable promise for revolutionizing treatment strategies for solid cancers.
Chimeric antigen receptor T-cell (CAR-T) therapy involves extracting a patient's T lymphocytes, genetically modifying them to recognize and destroy cancer cells [77]. CAR-T cells are highly beneficial due to their ability to provide both immediate and long-lasting effects, as they continue to proliferate through clonal expansion [78, 79]. Five generations of CAR-T cells have developed throughout time to increase their proliferative potential, decrease toxicity, and improve targeting accuracy. B-cell cancers can now be treated using second-generation CAR-T cells. Compared to the first generation, these cells have an extra costimulatory molecule that improves T-cell responses and persistence. An extra costimulatory domain speeds up tumor clearance even more in the third generation. The fourth generation, referred to as "armored CAR-T cells" or TRUCKs (T-cells Redirected for antigen-Unrestricted Cytokine-initiated Killing), may be useful in solid tumors because it uses an interleukin inducer to get past immunosuppressive components in TME [80]. The fifth generation, still in development, adds a signal transducer and activator of transcription 3 (STAT3) binding site to promote engagement with the JAK-STAT pathway, thereby enhancing immune stimulation [81]. Efforts to improve CAR-T cell therapies for PDAC and other solid tumors are extensive and focus on enhancing efficacy.
The goal of research on localized delivery strategies, like those used for glioblastoma, is to minimize systemic toxicity while more accurately delivering CAR-T cells to the tumor site. Furthermore, by enlisting local immune cells, armored CAR-T cells that produce cytokines have been demonstrated to fight the immunosuppressive TME. This strategy may increase efficacy even more when combined with other immunotherapies [82]. In a range of solid cancers, including gastrointestinal cancers research into "tandem CAR-T cells" that contain two different antibody fragments has also shown promise in enhancing the detection and elimination of tumors with heterogeneous antigen expression [83]. These developments show how CAR-T cell therapies are continuously being improved to meet the particular difficulties associated with treating solid tumors.

In this review, various mechanisms underlying vaccines and unique therapies for metastatic PC have been explored. The immune system’s feedback to TME plays a crucial part in influencing the metastatic potential of PC cells. Vaccines that stimulate a T-cell feedback have the potential to increase the effectiveness of immunotherapy. However, combining vaccine therapies with agents that target the TME to promote T-cell infiltration may amplify the ability to inhibit PC metastasis. Current strategy may further optimize the combination of drugs and vaccines for treating metastatic PC patients.

Acknowledgements

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Data and materials are available on request from the authors.

Ethical policy

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Author contributions

AFN contributed to draft, critical revision of the article and figure production; MA provided the idea and submitted the final version online.

Competing interests

I declare that there is no conflict of interest regarding the publication of this document.

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