Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive, with limited success in traditional therapies due to the fibrotic, immunosuppressive, pro-metastatic tumor microenvironment (TME), which collectively impede the drug accumulation and accelerate the tumor progression. In this work, we developed a PDAC-customized nutrient-mimicking reconstituted high-density lipoprotein (rHDL) capable of efficiently co-encapsulate versatile TME regulating cannabidiol and cytotoxic gemcitabine to simultaneously reprogram TME while suppressing PDAC progression. Specifically, a small-sized, nutrient-like rHDL was constructed to realize deep PDAC parenchyma penetration and efficient intra-tumoral uptake. Next, natural herbal compound cannabidiol was screened and incorporated into rHDL to regulate TME via attenuating fibrosis, reliving immunosuppression and mitigating metastatic tendency. At last, gemcitabine, the PDAC gold standard first-line therapy was co-delivered by the PDAC-customized rHDL to overcome drug resistance and amplify its PDAC suppression. Our findings demonstrate the feasibility of an integrated multi-stage TME regulation strategy for improved PDAC therapy, and might represent a modality in promoting chemotherapy against PDAC.

Activated RAS is a common driver of cancer that was considered undruggable for decades. Recent advances have enabled the development of RAS inhibitors, but the efficacy of these inhibitors remains limited by resistance. In this study, we developed a pan-RAS inhibitor, ADT-007, (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide, that binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 potently inhibited the growth of RAS-mutant cancer cells irrespective of the RAS mutation or isozyme. Wild-type RAS (RASWT) cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RASWT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, whereas insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases that were expressed in RASWT and normal cells but repressed in RAS-mutant cancer cells. ADT-007 displayed unique advantages over KRAS mutant-specific, pan-KRAS, and pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms that lead to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immunocompetent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancers. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth. Thus, ADT-007 has the potential to address the complex RAS mutational landscape of many human cancers and to improve treatment of RAS-driven tumors. Significance: ADT-007, a first-in-class pan-RAS inhibitor, has unique selectivity for cancer cells with mutant RAS or activated RAS protein and the capability to circumvent resistance to suppress tumor growth, supporting further development of ADT-007 analogs.

Intrahepatic cholangiocarcinoma (iCCA) denotes a rare, highly malignant, and heterogeneous class of primary liver adenocarcinomas exhibiting phenotypic characteristics of cholangiocyte differentiation. Among the distinctive pathological features of iCCA, one that differentiates the most common macroscopic subtype (eg, mass-forming type) of this hepatic tumor from conventional hepatocellular carcinoma is a prominent desmoplastic reaction manifested as a dense fibro-collagenous-enriched tumor stroma. Cancer-associated fibroblasts (CAFs) represent the most abundant mesenchymal cell type in the desmoplastic reaction. Although the protumor effects of CAFs in iCCA have been increasingly recognized, more recent cell lineage tracing studies, advanced single-cell RNA sequencing, and expanded biomarker analyses have provided new awareness into their ontogeny, as well as underscored their biological complexity as reflected by the presence of multiple subtypes. In addition, evidence supports CAFs' potential to display cancer-restrictive roles, including immunosuppression. However, CAFs also play important roles in facilitating metastasis, as exemplified by lymph node metastasis and peritoneal carcinomatosis, which are common in iCCA. Herein, the authors provide a timely appraisal of the origins and phenotypic and functional complexity of CAFs in iCCA, together with providing mechanistic insights into lymphangiogenesis and peritoneal metastasis relevant to this lethal human cancer.

Pancreatic ductal adenocarcinoma (PDAC) patients with tumors enriched for the basal-like molecular subtype exhibit enhanced resistance to standard-of-care treatments and have significantly worse overall survival compared with patients with classic subtype-enriched tumors. It is important to develop genomic resources, enabling identification of novel putative targets in a statistically rigorous manner.

We compiled a single-cell RNA sequencing (scRNA-seq) atlas of the human pancreas with 229 patient samples aggregated from publicly available raw data. We mapped cell type-specific scRNA-seq gene signatures in bulk RNA-seq (n = 744) and spatial transcriptomics (ST; n = 22) and performed validation using multiplex immunostaining.

Analysis of tumor cells from our scRNA-seq atlas revealed nine distinct populations, two of which aligned with the basal subtype, correlating with worse overall survival in bulk RNA-seq. Deconvolution identified one of the basal populations to be the predominant tumor subtype in nondissociated ST tissues and in vitro tumor cell and patient-derived organoid lines. We discovered a novel enrichment and spatial association of CXCL10+ cancer-associated fibroblasts with basal tumor cells. We identified that besides immune cells, ductal cells also express CXCR3, the receptor for CXCL10, suggesting a relationship between these cell types in the PDAC tumor microenvironment.

We show that our scRNA-seq atlas (700,000 cells), integrated with ST data, has increased statistical power and is a powerful resource, allowing for expansion of current subtyping paradigms in PDAC. We uncovered a novel signaling niche marked by CXCL10+ cancer-associated fibroblasts and basal tumor cells that could be explored for future targeted therapies.

Studies have implied that fibroblasts may act as regulators of immune cells in the tumor microenvironment (TME). We investigated the clinical relevance of fibroblast activation protein (FAP) positive stroma in high-grade serous ovarian cancer (HGSC) in relation to CD8+ lymphocyte's infiltration.

In a discovery cohort (N = 113) of HGSC, expression of FAP and CD8 in the TME was analyzed with immunohistochemistry. Results were correlated with overall survival (OS) and progression-free survival (PFS). The findings were validated in an independent cohort of HGSC (N = 121) and in public available datasets.

High infiltration of CD8+ cells in the TME of HGSC was found to be associated with longer OS, as previously known. Increased expression of FAP was associated with shorter median PFS (11.4 vs. 18.6 months) in tumors with high density of CD8+ cells (HR 4.03, CI 95 % 1.38-11.72, p = 0.01). Similarly, in the validation cohort, high intensity of FAP in cases with high density of CD8+ cells was associated with shorter OS, 31.5 vs 76.9 months (HR 2.83; 95 % CI 1.17-6.86, p = 0.02). The results were consistent in multivariable analyses. The association between high FAP expression and poor outcome in high density CD8 HGSC was also confirmed in publicly available datasets.

The TME infiltration of FAP-positive fibroblasts is associated with poor prognosis in HGSC with high CD8+ cells density. Targeting the FAP+ subset of fibroblasts may unlock the local immune-activation in the TME thus enhance the positive prognostic effect of T-cells in ovarian cancer.

Mutations in the KRAS gene are well-known tumourigenic drivers of colorectal, pancreatic and lung cancers. Mechanistically, these mutations promote uncontrolled cell proliferation and alter the tumour microenvironment during early carcinoma stages. Given their critical carcinogenic functions, significant progress has been made in developing KRAS inhibitors for cancer treatment. However, clinical applications of these KRAS inhibitor compounds are limited to specific cancer types which carry the relevant KRAS mutations. Additionally, clinical findings have shown that these compounds can induce moderate to serious side effects. Therefore, new approaches have emerged focusing on the development of universal therapeutics capable of targeting a wider range of KRAS mutations, minimising toxicity and enhancing the therapeutic efficacy. This review aims to examine these therapeutic strategies in the context of cancer treatment. It firstly provides an overview of fundamental KRAS biology within the cell signalling landscape and how KRAS mutations are associated with cancer pathogenesis. Subsequently, it introduces the development of current KRAS inhibitors which target certain KRAS mutants in different types of cancer. It then explores the potential of gene therapy approaches, including siRNA, miRNA and CRISPR methodologies. Furthermore, it discusses the use of lipid-based nanocarriers to deliver gene cargos for targeting KRAS gene mutants. Finally, it provides the insights into the future prospects for combatting KRAS mutation-associated cancers.

This review article summarizes the pathophysiological aspects of interleukins (ILs) including IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, and IL-10 in pancreatic cancer (PC).

Science Direct, PubMed, and Google Scholar were used for the literature review. The search was conducted until August 12, 2024, and particular keywords such as "Pancreatic Cancer," "Interleukins," "Pathophysiological Aspects," "Immunosuppression," "Invasiveness," and "Metastasis" were used. Focusing on interleukins related to pancreatic cancer, 61 original studies were included: 32 studies for human patients, 16 studies for animal models, and 13 studies for both animal models and human patients. All types of PC were considered. The timeframe of 1991 to 2024 was chosen for clinical studies.

In epithelial pancreatic tumors, IL-1 is a major inflammation factor. Serum concentrations of soluble interleukin-2-receptor were considerably greater in patients with PC and chronic pancreatitis than in healthy individuals. In comparison to controls, pancreatic cancer patients had considerably greater levels of macrophage colony-stimulating factor and significantly lower levels of stem cell factor and IL-3. The tissues and cells of pancreatic cancer have higher concentrations of IL-4 receptors. IL-5 has a role in the accumulation of pancreatic fibrosis. For individuals with pancreatic ductal adenocarcinoma (PDAC), a high serum level of IL-6 may be a separate risk factor for the development of widespread liver metastases. PDAC patients' peripheral blood mononuclear cells exhibit a substantial upregulation of IL-7 receptor. The role of IL-8 in the growth and spread of PC in humans. The miR-200a/β-catenin axis may be the mechanism by which IL-9 stimulates the proliferation and metastasis of PC cells. Blocking IL-10 in the local microenvironment appears to result in a significant reversal of tumor-induced immunosuppression.

The article concludes that interleukins 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 played significant roles in the pathogenesis of PC.

A noticeable characteristic of pancreatic ductal adenocarcinoma (PDAC) tumors is a dense tumor microenvironment with abundant and dense, desmoplastic stroma woven tightly with both cellular and matrix components. The high stromal density is associated with higher intratumor pressures which, until the last decade, was largely assumed to be tumor protective, confirmed by early studies demonstrating that altering the stroma was effective in genetically engineered models of PDAC. However, clinical trials using these approaches have been disappointing. There is increasing recognition that stroma heterogeneity is much greater than initially thought with an explosion of investigation into cancer-associated fibroblast (CAF) subpopulations led by experimental and single-cell transcriptomic studies. This review summarizes and attempts to harmonize the current transcriptomic data of CAF subpopulations. Understanding the heterogeneity of CAFs, the matrix, and other tumor microenvironment features will be critical to developing effective therapeutic approaches. Identifying model systems that best recapitulate the clinical behavior and treatment response of human PDAC will be important. Examining subpopulations as defined by clinical outcome will remain a critical step in defining clinically impactful CAF subtypes in larger clinical cohorts. The future of precision oncology in PDAC will depend on the integration of precision tumor epithelial and precision stroma approaches.

Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RAS WT cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RAS WT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, while insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases expressed in RAS WT and normal cells but repressed in RAS mutant cancer cells. ADT-007 binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 displayed unique advantages over mutant-specific KRAS and pan-KRAS inhibitors, as well as other pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms leading to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for RAS-driven cancers.

ADT-007 has unique pharmacological properties with distinct advantages over other RAS inhibitors by circumventing resistance and activating antitumor immunity. ADT-007 prodrugs and analogs with oral bioavailability warrant further development for RAS-driven cancers.

Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer-associated fibroblasts (CAF). The mechanisms underlying this conversion, including the regulation and function of fibroblast-derived cytokines, are poorly understood. Thus, efforts to therapeutically target CAFs have so far failed. Herein, we show that signals from epithelial cells expressing oncogenic KRAS-a hallmark pancreatic cancer mutation-activate fibroblast autocrine signaling, which drives the expression of the cytokine IL33. Stromal IL33 expression remains high and dependent on epithelial KRAS throughout carcinogenesis; in turn, environmental stress induces interleukin-33 (IL33) secretion. Using compartment-specific IL33 knockout mice, we observed that lack of stromal IL33 leads to profound reprogramming of multiple components of the pancreatic tumor microenvironment, including CAFs, myeloid cells, and lymphocytes. Notably, loss of stromal IL33 leads to an increase in CD8+ T-cell infiltration and activation and, ultimately, reduced tumor growth. Significance: This study provides new insights into the mechanisms underlying the programming of CAFs and shows that during this process, expression of the cytokine IL33 is induced. CAF-derived IL33 has pleiotropic effects on the tumor microenvironment, supporting its potential as a therapeutic target.

The ST6GAL1 sialyltransferase is overexpressed in multiple cancers, including pancreatic ductal adenocarcinoma (PDAC). ST6GAL1 adds an α2-6-linked sialic acid to N-glycosylated membrane receptors, which consequently modulates receptor structure and function. While many studies have investigated the effects of ST6GAL1 on cell phenotype, there is a dearth of knowledge regarding mechanisms that regulate ST6GAL1 expression. In the current study, we evaluated the regulation of ST6GAL1 by two pro-inflammatory cytokines, IL-1β and IL-6, which are abundant within the PDAC tumor microenvironment. Cytokine activity was monitored using the Suit-2 PDAC cell line and two Suit-2-derived metastatic subclones, S2-013 and S2-LM7AA. For all three cell models, treatment with IL-1β or IL-6 increased the expression of ST6GAL1 protein and mRNA. Specifically, IL-1β and IL-6 induced expression of the ST6GAL1 YZ mRNA isoform, which is driven by the P3 promoter. The ST6GAL1 H and X isoforms were not detected. Promoter reporter assays confirmed that IL-1β and IL-6 activated transcription from the P3 promoter. We then examined downstream signaling mechanisms. IL-1β is known to signal through the NFκB transcription factor, whereas IL-6 signals through the STAT3 transcription factor. CUT&RUN experiments revealed that IL-1β promoted the binding of NFκB to the ST6GAL1 P3 promoter, and IL-6 induced the binding of STAT3 to the P3 promoter. Finally, we determined that inhibitors of NFκB and STAT3 blocked the upregulation of ST6GAL1 stimulated by IL-1β and IL-6, respectively. Together, these results highlight a novel molecular pathway by which cytokines within the tumor microenvironment stimulate the upregulation of ST6GAL1 in PDAC cells.

Tumor immune resistance is recognized as a contributor to low survivorship in pancreatic ductal adenocarcinoma (PDAC). We developed a novel murine model of spontaneous PDAC clearance, generated by overexpressing interleukin-6 (IL-6) in orthotopically implanted PDAC cancer cells (OT-PDACIL6). Circulating IL-6 was 100-fold higher in OT-PDACIL6 than in OT-PDACparental mice. OT-PDACIL6 tumors were present at 5 days post-implantation, and undetectable by 10 days post implantation. Flow cytometry revealed increased T cells and NK cells, and decreased T regulatory cells in OT-PDACIL6 as compared to OT-PDACparental tumors. Increased lymphoid aggregates were apparent by histological assessment and may account for elevated T cell content. Antibody-based depletion of CD4+ and CD8+ T cells prevented tumor clearance and significantly reduced survival of OT-PDACIL6 mice. The anti-tumor immune response to OT-PDACIL6 rendered mice immune to re-challenge with OT-PDACparental tumors. In high concentrations, IL-6 acts in opposition to previously described pro-tumorigenic effects by enhancing the T cell-mediated anti-tumor response to PDAC.

Pancreatic ductal adenocarcinoma (PDAC) harbors a complex tumor microenvironment, and cross-talk among cells in the tumor microenvironment can contribute to drug resistance and relapse. Vasoactive intestinal peptide (VIP) is overexpressed in PDAC, and VIP receptors expressed on T cells are a targetable pathway that sensitizes PDAC to immunotherapy. In this study, we showed that pancreatic cancer cells engage in autocrine VIP signaling through VIP receptor 2 (VPAC2). High coexpression of VIP with VPAC2 correlated with reduced relapse-free survival in patients with PDAC. VPAC2 activation in PDAC cells upregulated Piwi-like RNA-mediated gene silencing 2, which stimulated cancer cell clonogenic growth. In addition, VPAC2 signaling increased expression of TGFβ1 to inhibit T-cell function. Loss of VPAC2 on PDAC cells led to reduced tumor growth and increased sensitivity to anti-PD-1 immunotherapy in mouse models of PDAC. Overall, these findings expand our understanding of the role of VIP/VPAC2 signaling in PDAC and provide the rationale for developing potent VPAC2-specific antagonists for treating patients with PDAC. Significance: Autocrine VIP signaling via VPAC2 promotes cancer cell growth and inhibits T-cell function in pancreatic ductal adenocarcinoma, highlighting its potential as a therapeutic target to improve pancreatic cancer treatment.

Despite the already dire impact of pancreatic cancer, a growing subset of patients with obesity exhibits an amplified risk of disease and worse outcomes. Mouse models have revealed that obesity is distinctly pathogenic, accelerating pancreatic ductal adenocarcinoma (PDAC) progression and inducing increased desmoplasia and myeloid cell infiltration in the tumor microenvironment. However, whether and how obesity-countering interventions, such as exercise, reverse the protumorigenic effects of obesity is incompletely understood. In this issue of Cancer Research, Pita-Grisanti and colleagues investigate the impact of physical activity (PA) in disrupting obesity-driven PDAC. Employing a variety of sophisticated models, including autochthonous genetically engineered mice, orthotopic syngeneic allografts, high-fat diet-induced obesity, and PA interventions in mice and humans, the authors found that PA impedes PDAC development in obese mice but does not impact the growth of advanced tumors. These antitumor effects correlated with reduced inflammation and fibrosis in the tumor microenvironment, a decline in high-fat diet-induced circulating inflammatory cytokines, and an increase in the IL15 signaling axis in white adipose tissue. Although adipose-targeted IL15 therapy was effective in suppressing advanced tumor growth in lean mice, obese mice were resistant to its therapeutic benefits. Together, the findings argue that PA delays obesity-driven early PDAC progression, implicating the preferential benefit of exercise as a preventative strategy. They further identify changes in obesity-associated local and systemic cytokine production as a possible mechanism for the antitumor effects of PA and help define context-specific determinants of response for emerging IL15-based immunotherapies. See related article by Pita-Grisanti et al., p. 3058.

This review comprehensively investigates the intricate interplay between small non-coding RNAs (sncRNAs) and pancreatic ductal adenocarcinoma (PDAC), a devastating malignancy with limited therapeutic options. Our analysis reveals the pivotal roles of sncRNAs in various facets of PDAC biology, spanning diagnosis, pathogenesis, drug resistance, and therapeutic strategies. sncRNAs have emerged as promising biomarkers for PDAC, demonstrating distinct expression profiles in diseased tissues. sncRNA differential expression patterns, often detectable in bodily fluids, hold potential for early and minimally invasive diagnostic approaches. Furthermore, sncRNAs exhibit intricate involvement in PDAC pathogenesis, regulating critical cellular processes such as proliferation, apoptosis, and metastasis. Additionally, mechanistic insights into sncRNA-mediated pathogenic pathways illuminate novel therapeutic targets and interventions. A significant focus of this review is dedicated to unraveling sncRNA mechanisms underlying drug resistance in PDAC. Understanding these mechanisms at the molecular level is imperative for devising strategies to overcome drug resistance. Exploring the therapeutic landscape, we discuss the potential of sncRNAs as therapeutic agents themselves as their ability to modulate gene expression with high specificity renders them attractive candidates for targeted therapy. In summary, this review integrates current knowledge on sncRNAs in PDAC, offering a holistic perspective on their diagnostic, pathogenic, and therapeutic relevance. By elucidating the roles of sncRNAs in PDAC biology, this review provides valuable insights for the development of novel diagnostic tools and targeted therapeutic approaches, crucial for improving the prognosis of PDAC patients.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive form of cancer with a low survival rate. A successful treatment strategy should not be limited to targeting cancer cells alone, but should adopt a more comprehensive approach, taking into account other influential factors. These include the extracellular matrix (ECM) and immune microenvironment, both of which are integral components of the tumor microenvironment. The present review describes the roles of pancreatic stellate cells, differentiated cancer‑associated fibroblasts and the interleukin family, either independently or in combination, in the progression of precursor lesions in pancreatic intraepithelial neoplasia and PDAC. These elements contribute to ECM deposition and immunosuppression in PDAC. Therapeutic strategies that integrate interleukin and/or stromal blockade for PDAC immunomodulation and fibrogenesis have yielded inconsistent results. A deeper comprehension of the intricate interplay between fibrosis, and immune responses could pave the way for more effective treatment targets, by elucidating the mechanisms and causes of ECM fibrosis during PDAC progression.

Currently, creating more effector T cells and augmenting their functions is a focal point in pancreatic ductal adenocarcinoma (PDAC) treatment research. T cell immunoglobulin domain and mucin domain molecule 4 (TIM-4), known for promoting cancer progression in various malignancies, is implicated in the suppressive immune microenvironment of tumors. Analyzing of the role of TIM-4 in the immune regulation of PDAC can offer novel insights for immune therapy.

We analyzed the TIM-4 expression in tumor specimens from PDAC patients. Meanwhile, multiple fluorescent immunohistochemical staining was used to study the distribution characteristics of TIM-4, and through tissue microarrays, we explored its correlation with patient prognosis. The influence of TIM-4 overexpression on cell function was analyzed using RNA-seq. Flow cytometry and ELISA were used for verification. Finally, the relationship between TIM-4 and T lymphocytes was analyzed by tissue microarray, and the impacts of TIM-4 on T cell subsets were observed by cell coculture technology and a mouse pancreatic cancer in situ model.

In PDAC, TIM-4 is mainly expressed in tumor cells and negatively correlated with patient prognosis. TIM-4 influences the differentiation of Treg by inhibiting IL-6 secretion in pancreatic cancer cells and facilitates the proliferation of pancreatic cancer in mice. Additionally, the mechanism may be through the CD8+ effector T cells (CD8+Tc).

TIM-4 has the potential to be an immunotherapeutic target or to improve the efficacy of chemotherapy for PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a dismal five-year survival rate of less than 10%. Neutrophils are key components of the innate immune system, playing a pivotal role in the PDAC immune microenvironment.

This review provides a comprehensive survey of the pivotal involvement of neutrophils in the tumorigenesis and progression of PDAC. Furthermore, it synthesizes preclinical and clinical explorations aimed at targeting neutrophils within the milieu of PDAC, subsequently proposing a conceptual framework to propel further inquiry focused on enhancing the therapeutic efficacy of PDAC through neutrophil-targeted strategies. PubMed and Web of Science databases were utilized for researching neutrophils in pancreatic cancer publications prior to 2024.

Neutrophils play roles in promoting tumor growth and metastasis in PDAC and are associated with poor prognosis. However, the heterogeneity and plasticity of neutrophils and their complex relationships with other immune cells and extracellular matrix also provide new insights for immunotherapy targeting neutrophils to achieve a better prognosis for PDAC.

Pancreatic ductal adenocarcinoma remains one of the most lethal solid tumors due to its local aggressiveness and metastatic potential, with a 5-year survival rate of only 13%. A robust connection between pancreatic cancer microenvironment and tumor progression exists, as well as resistance to current anticancer treatments. Pancreatic cancer has a complex tumor microenvironment, characterized by an intricate crosstalk between cancer cells, cancer-associated fibroblasts and immune cells. The complex composition of the tumor microenvironment is also reflected in the diversity of its acellular components, such as the extracellular matrix, cytokines, growth factors and secreted ligands involved in signaling pathways. Desmoplasia, the hallmark of the pancreatic cancer microenvironment, contributes by creating a dense and hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance and suppresses anti-tumor immune invasion. We discuss the complex crosstalk among tumor microenvironment components and explore therapeutic strategies and opportunities in pancreatic cancer research. Better understanding of the tumor microenvironment and its influence on pancreatic cancer progression could lead to potential novel therapeutic options, such as integration of immunotherapy and cytokine-targeted treatments.

Human microbiomes, considered as a new emerging and enabling cancer hallmark, are increasingly recognized as critical effectors in cancer development and progression. Manipulation of microbiome revitalizing anticancer therapy from natural products shows promise toward improving cancer outcomes. Herein, we summarize our current understanding of the human microbiome-driven molecular mechanisms impacting cancer progression and anticancer therapy. We highlight the potential translational and clinical implications of natural products for cancer prevention and treatment by developing targeted therapeutic strategies as adjuvants for chemotherapy and immunotherapy against tumorigenesis. The challenges and opportunities for future investigations using modulation of the microbiome for cancer treatment are further discussed in this review.

Pancreatic cancer is difficult to diagnose early and progresses rapidly. Researchers have found that a cytokine called Interleukin-6 (IL-6) is involved in the entire course of pancreatic cancer, promoting its occurrence and development. From the earliest stages of pancreatic intraepithelial neoplasia to the invasion and metastasis of pancreatic cancer cells and the appearance of tumor cachexia, IL-6 drives oncogenic signal transduction pathways and immune escape that accelerate disease progression. IL-6 is considered a biomarker for pancreatic cancer diagnosis and prognosis, as well as a potential target for treatment. IL-6 antibodies are currently being explored as a hot topic in oncology. This article aims to systematically explain how IL-6 induces the deterioration of normal pancreatic cells, with the goal of finding a breakthrough in pancreatic cancer diagnosis and treatment.

Cancer is a progressive disease that can develop and evolve over decades, with inflammation playing a central role at each of its stages, from tumor initiation to metastasis. In this context, macrophages represent well-established bridges reciprocally linking inflammation and cancer via an array of diverse functions that have spurred efforts to classify them into subtypes. Here, we discuss the intertwines between macrophages, inflammation, and cancer with an emphasis on temporal dynamics of macrophage diversity and functions in pre-malignancy and cancer. By instilling temporal dynamism into the more static classic view of tumor-associated macrophage biology, we propose a new framework to better contextualize their significance in the inflammatory processes that precede and result from the onset of cancer and shape its evolution.

Cancer-associated fibroblasts (CAFs), a phenotypically and functionally heterogeneous stromal cell, are one of the most important components of the tumour microenvironment. Previous studies have consolidated it as a promising target against cancer. However, variable therapeutic efficacy-both protumor and antitumor effects have been observed not least owing to the strong heterogeneity of CAFs. Over the past 10 years, advances in single-cell RNA sequencing (scRNA-seq) technologies had a dramatic effect on biomedical research, enabling the analysis of single cell transcriptomes with unprecedented resolution and throughput. Specifically, scRNA-seq facilitates our understanding of the complexity and heterogeneity of diverse CAF subtypes. In this review, we discuss the up-to-date knowledge about CAF heterogeneity with a focus on scRNA-seq perspective to investigate the emerging strategies for integrating multimodal single-cell platforms. Furthermore, we summarized the clinical application of scRNA-seq on CAF research. We believe that the comprehensive understanding of the heterogeneity of CAFs form different visions will generate innovative solutions to cancer therapy and achieve clinical applications.

Peritoneal carcinomatosis (PC) is a complex manifestation of abdominal cancers, with a poor prognosis and limited treatment options. Recent work identifying high concentrations of the cytokine interleukin-6 (IL-6) and its soluble receptor (sIL-6-Rα) in the peritoneal cavity of patients with PC has highlighted this pathway as an emerging potential therapeutic target. This review article provides a comprehensive overview of the current understanding of the potential role of IL-6 in the development and progression of PC. We discuss mechansims by which the IL-6 pathway may contribute to peritoneal tumor dissemination, mesothelial adhesion and invasion, stromal invasion and proliferation, and immune response modulation. Finally, we review the prospects for targeting the IL-6 pathway in the treatment of PC, focusing on common sites of origin, including ovarian, gastric, pancreatic, colorectal and appendiceal cancer, and mesothelioma.

Historically, KRAS has been considered 'undruggable' inspite of being one of the most frequently altered oncogenic proteins in solid tumors, primarily due to the paucity of pharmacologically 'druggable' pockets within the mutant isoforms. However, pioneering developments in drug design capable of targeting the mutant KRAS isoforms especially KRASG12C-mutant cancers, have opened the doors for emergence of combination therapies comprising of a plethora of inhibitors targeting different signaling pathways. SHP2 signaling pathway, primarily known for activation of intracellular signaling pathways such as KRAS has come up as a potential target for such combination therapies as it emerged to be the signaling protein connecting KRAS and the immune signaling pathways and providing the link for understanding the overlapping regions of RAS/ERK/MAPK signaling cascade. Thus, SHP2 inhibitors having potent tumoricidal activity as well as role in immunomodulation have generated keen interest in researchers to explore its potential as combination therapy in KRAS mutant solid tumors. However, the excitement with these combination therapies need to overcome challenges thrown up by drug resistance and enhanced toxicity. In this review, we will discuss KRAS and SHP2 signaling pathways and their roles in immunomodulation and regulation of tumor microenvironment and also analyze the positive effects and drawbacks of the different combination therapies targeted at these signaling pathways along with their present and future potential to treat solid tumors.

The interleukin-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine and a naturally occurring antagonist of the IL-1 receptor. It effectively counteracts the IL-1 signaling pathway mediated by IL-1α/β. Over the past few decades, accumulating evidence has suggested that IL-1 signaling plays an essential role in tumor formation, growth, and metastasis. Significantly, anakinra, the first United States Food and Drug Administration (FDA)-approved IL-1Ra drug, has demonstrated promising antitumor effects in animal studies. Numerous clinical trials have subsequently incorporated anakinra into their cancer treatment protocols. In this review, we comprehensively discuss the research progress on the role of IL-1 in tumors and summarize the significant contribution of IL-1Ra (anakinra) to tumor immunity. Additionally, we analyze the potential value of IL-1Ra as a biomarker from a clinical perspective. This review is aimed to highlight the important link between inflammation and cancer and provide potential drug targets for future cancer therapy.

Early detection of pancreatic cancer is crucial for improving patient outcomes, and identifying reliable biomarkers is a critical research area in this field. Galectin-3 (Gal-3) is a promising candidate for utilisation as a diagnostic biomarker in early-stage pancreatic cancer. This review aims to explore the potential of Gal-3 in pancreatic cancer diagnosis and its implications for precision medicine. Rigorous validation studies are essential to establish the clinical utility of Gal-3, including large-scale investigations to assess its sensitivity, specificity, and predictive value. Combining Gal-3 with existing biomarkers and advanced imaging techniques may enhance the accuracy of early detection. Moreover, Gal-3 holds promise for risk stratification, enabling the identification of high-risk individuals who could benefit from intensified surveillance and early interventions. However, challenges in standardised testing protocols, establishing reference ranges, assay reliability, workflow integration, cost-effectiveness, and healthcare provider education must be addressed for successful implementation. Despite these challenges, Gal-3 presents significant implications for precision medicine in pancreatic cancer management. By unravelling its potential and overcoming the hurdles, Gal-3 could revolutionise early detection, risk stratification, and personalised approaches in pancreatic cancer care. Collaborative efforts and continued research will be crucial in harnessing the full potential of Gal-3 as a diagnostic biomarker for early-stage pancreatic cancer.

Benzodiazepines (BZDs) are commonly prescribed for pancreatic cancer patients. To investigate the correlation between BZDs and survival outcomes a recent study by Cornwell et al. found that lorazepam (LOR) correlates with poor survival. The mechanistic study shows that LOR increases interleukin 6 (IL6) expression in cancer-associated fibroblasts via GPR68.

This research investigates the association between benzodiazepines (BZD) and cancer patient survival outcomes, the pancreatic cancer tumor microenvironment, and cancer-associated fibroblast (CAF) signaling.

Multivariate Cox regression modeling was used to retrospectively measure associations between Roswell Park cancer patient survival outcomes and BZD prescription records. IHC, H&E, Masson's trichrome, RNAscope, and RNA sequencing were used to evaluate the impact of lorazepam (LOR) on the murine PDAC tumor microenvironment. ELISA and qPCR were used to determine the impact of BZDs on IL6 expression or secretion by human-immortalized pancreatic CAFs. PRESTO-Tango assays, reanalysis of PDAC single-cell sequencing/TCGA data sets, and GPR68 CRISPRi knockdown CAFs were used to determine the impact of BZDs on GPR68 signaling.

LOR is associated with worse progression-free survival (PFS), whereas alprazolam (ALP) is associated with improved PFS, in pancreatic cancer patients receiving chemotherapy. LOR promotes desmoplasia (fibrosis and extracellular matrix protein deposition), inflammatory signaling, and ischemic necrosis. GPR68 is preferentially expressed on human PDAC CAFs, and n-unsubstituted BZDs, such as LOR, significantly increase IL6 expression and secretion in CAFs in a pH and GPR68-dependent manner. Conversely, ALP and other GPR68 n-substituted BZDs decrease IL6 in human CAFs in a pH and GPR68-independent manner. Across many cancer types, LOR is associated with worse survival outcomes relative to ALP and patients not receiving BZDs.

We demonstrate that LOR stimulates fibrosis and inflammatory signaling, promotes desmoplasia and ischemic necrosis, and is associated with decreased pancreatic cancer patient survival.

Hyperinsulinemia, hyperglucagonemia, and low-grade inflammation are frequently presented in obesity and type 2 diabetes (T2D). The pathogenic regulation between hyperinsulinemia/insulin resistance (IR) and low-grade inflammation is well documented in the development of diabetes. However, the cross-talk of hyperglucagonemia with low-grade inflammation during diabetes progression is poorly understood. In this study, we investigated the regulatory role of proinflammatory cytokine interleukin-6 (IL-6) on glucagon secretion.

The correlations between inflammatory cytokines and glucagon or insulin were analyzed in rhesus monkeys and humans. IL-6 signaling was blocked by IL-6 receptor-neutralizing antibody tocilizumab in obese or T2D rhesus monkeys, glucose tolerance was evaluated by intravenous glucose tolerance test (IVGTT). Glucagon and insulin secretion were measured in isolated islets from wild-type mouse, primary pancreatic α-cells and non-α-cells sorted from GluCre-ROSA26EYFP (GYY) mice, in which the enhanced yellow fluorescent protein (EYFP) was expressed under the proglucagon promoter, by fluorescence-activated cell sorting (FACS). Particularly, glucagon secretion in α-TC1 cells treated with IL-6 was measured, and RNA sequencing was used to screen the mediator underlying IL-6-induced glucagon secretion. SLC39A5 was knocking-down or overexpressed in α-TC1 cells to determine its impact in glucagon secretion and cytosolic zinc density. Dual luciferase and chromatin Immunoprecipitation were applied to analyze the signal transducer and activator of transcription 3 (STAT3) in the regulation of SLC39A5 transcription.

Plasma IL-6 correlate positively with plasma glucagon levels, but not insulin, in rhesus monkeys and humans. Tocilizumab treatment reduced plasma glucagon, blood glucose and HbA1c in spontaneously obese or T2D rhesus monkeys. Tocilizumab treatment also decreased glucagon levels during IVGTT, and improved glucose tolerance. Moreover, IL-6 significantly increased glucagon secretion in isolated islets, primary pancreatic α-cells and α-TC1 cells. Mechanistically, we found that IL-6-activated STAT3 downregulated the zinc transporter SLC39A5, which in turn reduced cytosolic zinc concentration and ATP-sensitive potassium channel activity and augmented glucagon secretion.

This study demonstrates that IL-6 increases glucagon secretion via the downregulation of zinc transporter SLC39A5. This result revealed the molecular mechanism underlying the pathogenesis of hyperglucagonemia and a previously unidentified function of IL-6 in the pathophysiology of T2D, providing a potential new therapeutic strategy of targeting IL-6/glucagon to preventing or treating T2D.

Cancer-associated fibroblasts (CAF) are a major cell type in the stroma of solid tumors and can exert both tumor-promoting and tumor-restraining functions. CAF heterogeneity is frequently observed in pancreatic ductal adenocarcinoma (PDAC), a tumor characterized by a dense and hypoxic stroma that features myofibroblastic CAFs (myCAF) and inflammatory CAFs (iCAF) that are thought to have opposing roles in tumor progression. While CAF heterogeneity can be driven in part by tumor cell-produced cytokines, other determinants shaping CAF identity and function are largely unknown. In vivo, we found that iCAFs displayed a hypoxic gene expression and biochemical profile and were enriched in hypoxic regions of PDAC tumors, while myCAFs were excluded from these regions. Hypoxia led fibroblasts to acquire an inflammatory gene expression signature and synergized with cancer cell-derived cytokines to promote an iCAF phenotype in a HIF1α-dependent fashion. Furthermore, HIF1α stabilization was sufficient to induce an iCAF phenotype in stromal cells introduced into PDAC organoid cocultures and to promote PDAC tumor growth. These findings indicate hypoxia-induced HIF1α as a regulator of CAF heterogeneity and promoter of tumor progression in PDAC.

Hypoxia in the tumor microenvironment of pancreatic cancer potentiates the cytokine-induced inflammatory CAF phenotype and promotes tumor growth. See related commentary by Fuentes and Taniguchi, p. 1560.

Previous studies have confirmed that bisphenol A (BPA) induced immune toxicity and affected diseases, however, the underlying mechanism remains unknown. In the present study, zebrafish was employed as the model to assess the immunotoxicity and the potential disease risk of BPA exposure. Upon BPA exposure, a series of abnormalities were found, which included the increased oxidative stress, damaged innate and adaptive immune functions and the elevated insulin and blood glucose levels. According to the target prediction and RNA sequencing data of BPA, the differential expression genes were found enriched in immune- and pancreatic cancer-related pathway and process, and the potential role of stat3 in the regulation of these processes was revealed. The key immune- and pancreatic cancer-related genes were selected for further confirmation by RT-qPCR. Based on the changes in the expression levels of these genes, our hypothesis that BPA induced the occurrence of pancreatic cancer by modulating immune responses was further evidenced. Deeper mechanism was further disclosed by molecular dock simulation and survival analysis of key genes, proving that BPA stably bound to STAT3 and IL10 and STAT3 may serve as the target of BPA-inducing pancreatic cancer. These results are of great significance in deepening the molecular mechanism of immunotoxicity induced by BPA and our understanding of the risk assessment of contaminants.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of <10%. Aberrant activation or elevated expression of the tyrosine kinase c-SRC (SRC) is frequently observed in PDAC and is associated with a poor prognosis. Preclinical studies have revealed a multifaceted role for SRC activation in PDAC, including promoting chronic inflammation, tumor cell proliferation and survival, cancer cell stemness, desmoplasia, hypoxia, angiogenesis, invasion, metastasis, and drug resistance. Strategies to inhibit SRC signaling include suppressing its catalytic activity, inhibiting protein stability, or by interfering with signaling components of the SRC signaling pathway including suppressing protein interactions of SRC. In this review, we discuss the molecular and immunological mechanisms by which aberrant SRC activity promotes PDAC tumorigenesis. We also provide a comprehensive update of SRC inhibitors in the clinic, and discuss the clinical challenges associated with targeting SRC in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging disease usually diagnosed at advanced or metastasized stage. By this year end, there are an expected increase in 62,210 new cases and 49,830 deaths in the United States, with 90% corresponding to PDAC subtype alone. Despite advances in cancer therapy, one of the major challenges combating PDAC remains tumor heterogeneity between PDAC patients and within the primary and metastatic lesions of the same patient. This review describes the PDAC subtypes based on the genomic, transcriptional, epigenetic, and metabolic signatures observed among patients and within individual tumors. Recent studies in tumor biology suggest PDAC heterogeneity as a major driver of disease progression under conditions of stress including hypoxia and nutrient deprivation, leading to metabolic reprogramming. We therefore advance our understanding in identifying the underlying mechanisms that interfere with the crosstalk between the extracellular matrix components and tumor cells that define the mechanics of tumor growth and metastasis. The bilateral interaction between the heterogeneous tumor microenvironment and PDAC cells serves as another important contributor that characterizes the tumor-promoting or tumor-suppressing phenotypes providing an opportunity for an effective treatment regime. Furthermore, we highlight the dynamic reciprocating interplay between the stromal and immune cells that impact immune surveillance or immune evasion response and contribute towards a complex process of tumorigenesis. In summary, the review encapsulates the existing knowledge of the currently applied treatments for PDAC with emphasis on tumor heterogeneity, manifesting at multiple levels, impacting disease progression and therapy resistance under stress.

Pancreatic cancer (PC) is a challenging diagnosis that is yet to benefit from the advancements in immuno-oncologic treatments. Irreversible electroporation (IRE), a non-thermal method of tumor ablation, is used in treatment of select patients with locally-advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate β-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment β-glucan induced trained immunity in the treatment of PC.

β-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and antitumor function after exposure to ablated and unablated tumor-conditioned media. β-Glucan and IRE combination therapy was tested in an orthotopic murine PC model in wild-type and Rag-/- mice. Tumor immune phenotypes were assessed by flow cytometry. Effect of oral β-glucan in the murine pancreas was evaluated and used in combination with IRE to treat PC. The peripheral blood of patients with PC taking oral β-glucan after IRE was evaluated by mass cytometry.

IRE-ablated tumor cells elicited a potent trained response ex vivo and augmented antitumor functionality. In vivo, β-glucan in combination with IRE reduced local and distant tumor burden prolonging survival in a murine orthotopic PC model. This combination augmented immune cell infiltration to the PC tumor microenvironment and potentiated the trained response from tumor-infiltrating myeloid cells. The antitumor effect of this dual therapy occurred independent of the adaptive immune response. Further, orally administered β-glucan was identified as an alternative route to induce trained immunity in the murine pancreas and prolonged PC survival in combination with IRE. β-Glucan in vitro treatment also induced trained immunity in peripheral blood monocytes obtained from patients with treatment-naïve PC. Finally, orally administered β-glucan was found to significantly alter the innate cell landscape within the peripheral blood of five patients with stage III locally-advanced PC who had undergone IRE.

These data highlight a relevant and novel application of trained immunity within the setting of surgical ablation that may stand to benefit patients with PC.

Increasing evidence has demonstrated the important roles of exosomes during pancreatic cancer development. However, the effects of pancreatic cancer exosomes (PC-exos) on adipocytes remain largely unknown. Here, we used mass-spectrometry-based lipidomics to identify lipids that were changed in adipocytes after exposure to PC-exos, and we found that triglyceride (TG) reduction was the most significant, which might be induced by increased lipolysis because the number of large lipid droplets increased while small ones decreased. Additionally, abdominal adipocytes in mice injected with PC-exos had a relatively smaller size. Mechanistically, we found that genes involved in metabolism and inflammation were up-regulated, among which increase of IL-6 was significant, and we then found IL-6 promoted lipolysis. To our knowledge, this is the first study on the lipidomics changes of adipocytes after PC-exos treatment.