Pancreatic cancer is a highly aggressive gastrointestinal malignancy, often termed the "king of cancers" due to its notoriously high mortality rate. Its clinical characteristics, including late diagnosis, low surgical resectability, high recurrence rates, significant chemoresistance, and poor prognosis have collectively driven the persistent rise in incidence and mortality. Despite ongoing advancements in therapeutic strategies, the management of pancreatic cancer, particularly at advanced stages, remains challenging. Chemotherapy remains the mainstay of current treatment. However, the prevalent problem of chemotherapy resistance poses a significant obstacle to effective treatment. Metabolic reprogramming, characterized by alterations in glucose metabolism, lipid biosynthesis, and amino acid utilization, supports the high energy demands and rapid proliferation of cancer cells. Emerging evidence suggests that these metabolic changes, possibly mediated by epigenetic mechanisms, also contribute to tumorigenesis and metastasis. These findings highlight the critical role of metabolic alterations in pancreatic cancer pathogenesis. This review explores the relationship between metabolic reprogramming and chemotherapy resistance, discussing underlying mechanisms and summarizing preclinical studies and drug development targeting metabolism. The aim is to provide a comprehensive perspective on potential therapeutic strategies for pancreatic cancer.

Ferroptosis in the tumor microenvironment (TME) plays a crucial role in the development, metastasis, immune escape, and drug resistance of various types of cancer. A better understanding of ferroptosis in the TME could illuminate novel aspects of this process and promote the development of targeted therapies. Compelling evidence indicates that exosomes are key mediators in regulating the TME. In this respect, it is now understood that exosomes can deliver biologically functional molecules to recipient cells, influencing cancer progression by reprogramming the metabolism of cancer cells and their surrounding stromal cells through ferroptosis. In this review, we focus on the role of exosomes in the TME and describe how they contribute to tumor reprogramming, immunosuppression, and the formation of pre-metastatic niches through ferroptosis. In addition, we highlight exosome-mediated ferroptosis as a potential target for cancer therapy and discuss strategies employing exosomes in ferroptosis treatment. Finally, we outline the current applications and challenges of targeted exosome-mediated ferroptosis therapy in tumor immunotherapy and chemotherapy. Our aim is to advance research on the link between exosomes and ferroptosis in the TME, and we pose questions to guide future studies in this area.

This study revealed the prospective biological role and fundamental mechanisms of hypoxia-induced lncRNA-MANCR (MANCR), which is notably upregulated in pancreatic cancer (PC). This work uncovered the potential biological function and underlying mechanisms of hypoxia-induced MANCR, which is significantly elevated in PC. Microarray assays confirmed MANCR expression in the tissues of patients with PC and patients with chronic pancreatitis (CP), which positively correlated with sirtuin-1 (SIRT1) mRNA levels. Chromatin immunoprecipitation and luciferase assays were employed to gauge binding within the hypoxia-inducible factor-1α (HIF-1α)/MANCR/miRNA-494/SIRT1 pathway. Additionally, the association between MANCR expression and the clinical outcomes of patients with PC was confirmed. MANCR is significantly upregulated in PC cells under hypoxic conditions, which is closely linked to poor prognosis in patients with PC. Depletion of MANCR repressed in vitro proliferation, migration, and invasion of PC cells and in vivo growth of PC xenograft tumours. We further demonstrated that MANCR is localised in the cytoplasm and competitively binds miR-494, which directly targets SIRT1. Mechanically, the overexpression of SIRT1 improved the stability of the HIF-1α protein through deacetylation, leading to enhanced HIF-1α assembly. Moreover, MANCR underwent transcriptional regulation by HIF-1α in a hypoxic setting. This modulation was ascribed to HIF-1α binding to hypoxia response elements present in the MANCR promoter sequence. Data revealed the potential possibility of feedback between MANCR and HIF-1α, which may be conducive to hypoxia-induced oncogenicity and PC tumorigenesis, thereby providing a suitable therapeutic target.

Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated.

In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs.

Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial-mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1-5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment.

We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable challenge due to its late diagnosis and intrinsic treatment resistance, exacerbates by its development from chronic inflammation to cancer transition (ICT). Here, this investigation aims to develop and evaluate ABSi-148, a novel near-infrared (NIR) agent targeting hypoxic carbonic anhydrase IX (CA IX), for its potential applications in ICT imaging and even PDAC treatment. ABSi-148 is synthesized from 4-(2-Aminoethyl) benzene sulfonamide (ABS), a sulfonamide derivative, conjugating with MHI-148 dye with merits of exceptional NIR-emitting traits, high biocompatibility, and deep tissue penetration imaging capability. It selectively accumulates in CoCl2-induced pancreatic stellate cells and pancreatic cancer cells via binding with transmembrane CA IX in vitro. Meanwhile, ABSi-148 effectively visualizes the early pancreatic lesion, and its long-term administration inhibits the progression of hypoxia-related fibrosis involved in pancreatic intraepithelial neoplasias (PanINs), and even PDAC progression in vivo. Besides, ABSi-148 monitors treatment efficacy and localizes hypoxic tumor regions, enhancing survival in tamoxifen combined with caerulein-induced KPC mice. Overall, ABSi-148 emerges as a theranostic NIR agent for precise diagnosis and targeted therapy in ICT of PDAC, promising to alleviate tumor progression and enhancing outcomes.

Pancreatic cancer (PC), characterized by the absence of effective biomarkers and therapies, remains highly fatal. Data regarding the correlations between PC risk and individual plasma proteome known for minimally invasive biomarkers are scarce. Here, we analyzed 1,345 human plasma proteins using proteome-wide association studies, identifying 78 proteins significantly associated with PC risk. Of these, four proteins (ROR1, FN1, APOA5, and ABO) showed the most substantial causal link to PC, confirmed through Mendelian randomization and colocalization analyses. Data from two clinical cohorts further demonstrated that FN1 and ABO were notably overexpressed in both blood and tumor samples from PC patients, compared to healthy controls or para-tumor tissues. Additionally, elevated FN1 and ABO levels correlated with shorter median survival in patients. Multiple drugs targeting FN1 or ROR1 are available or in clinical trials. These findings suggest that plasma protein FN1 associated with PC holds potential as both prognostic biomarkers and therapeutic targets.

Non-coding RNAs (ncRNAs) are sequences that do not encode for proteins and play key roles in different cellular processes, including cell proliferation and differentiation. On the other hand, connexins (Cxs) are transmembrane proteins that principally allow intercellular communication. In pathological conditions such as cancer, there is a deregulation in the expression and/or function of ncRNAs and Cxs, which in turn leads to an enhancement in the aggressive phenotype, such as a greater proliferative and invasive capacity. This suggests a plausible interplay between ncRNAs and Cxs. Based on that, this review aims to summarize the current knowledge regarding this relationship and to analyze how it may influence the development of aggressive traits in cancer cells and the clinicopathological features of cancer patients. Finally, we discuss the potential of ncRNAs and Cxs as promising clinical biomarkers for cancer diagnosis, prognosis, and therapeutic targeting.

Pancreatic ductal adenocarcinoma (PDAC) poses significant therapeutic challenges due to excessive hyaluronic acid (HA) accumulation, which impedes drug delivery. Here, we present a targeted approach to reduce HA production by specifically silencing glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1), a key enzyme of the hexosamine biosynthesis pathway (HBP) in pancreatic cancer cells. An engineered liposomal system for siGFAT1 delivery, PMLip@siGFAT1, characterized by macrophage membrane camouflage, LFC131 peptide-mediated targeting, and calcium phosphate (CaP) as the core, was designed to ensure prolonged circulation, enhanced inflamed vascular endothelial penetration, and subsequent effective tumor cell uptake and endosomal escape. Consequently, PMLip@siGFAT1 markedly downregulated the HA level in the PDAC microenvironment, decompressing the tumor vasculature and weakening the stromal barrier, which in turn improved the permeability of chemotherapeutics. In combination with Doxil, PMLip@siGFAT1 demonstrated potent antitumor efficacy with minimal systemic toxicity. Importantly, unlike PEGPH20 (hyaluronidase), PMLip@siGFAT1 reduced tumor invasiveness, while preserving skeletal muscle integrity. These findings highlight that PMLip@siGFAT1 holds great potential to revitalize HA downregulation strategies in pancreatic cancer for enhanced drug delivery and efficacy.

Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.

Circular RNAs (circRNAs) are a class of novel RNA molecules featured by single-strand covalently closed circular structure, which not only are extensively found in eukaryotes and are highly conserved, but also conduct paramount roles in the occurrence and progression of pancreatic cancer (PC) through diverse mechanisms. As recent studies have demonstrated, circRNAs typically exhibit tissue-specific and cell specific expression patterns, with strong potential as biomarkers for disease diagnosis and prognosis. On the basis of their localization and specific interactions with DNA, RNA, and proteins, circRNAs are considered to possess specific biological functions by acting as microRNA (miRNA) sponges, RNA binding protein (RBP) sponges, transcriptional regulators, molecular scaffolds and translation templates. On that account, further addressing the technical difficulties in the detection and research of circRNAs and filling gaps in their biological knowledge will definitely push ahead this comparatively young research field and bring circRNAs to the forefront of clinical practice. Thus, this review systematically summarizes the biogenesis, function, molecular mechanisms, biomarkers and therapeutic targets of circRNAs in PC.

The emergence of immunotherapies has revolutionized cancer treatment by leveraging the immune system to target malignancies, offering new hope where traditional therapies often fall short. Within this context, hyperthermia (HT) has re-emerged as a promising adjunctive treatment, capable of enhancing the effectiveness of radiotherapy, chemotherapy, and immunotherapy. HT influences both the innate and adaptive immune systems, enhancing the activity of immune cells such as neutrophils, NK cells, and dendritic cells, while also modulating the tumor microenvironment (TME) to promote immunogenic cell death (ICD) and reduce immunosuppressive conditions. These effects contribute to the transformation of immunologically "cold" tumors into "hot" tumors, making them more susceptible to immune-mediated destruction. Furthermore, HT can amplify the efficacy of immune checkpoint inhibitors (ICIs) by improving immune cell infiltration, inducing damage-associated molecular pattern (DAMP) release, and enhancing antigen presentation. Preclinical and clinical studies support the combination of HT with ICIs, demonstrating improved outcomes in otherwise resistant tumors. However, the full therapeutic potential of the different technologies allowing to apply HT remains to be fully understood, and further research is needed to optimize treatment protocols, explore the differential impacts of local versus whole-body hyperthermia, and identify biomarkers for patient stratification. This review underscores the multifaceted role of HT in immunity and its potential to significantly enhance the efficacy of immunotherapy.

The treatment of pancreatic cancer faces significant challenges due to connective tissue hyperplasia and severe hypoxia. Unlike oxygen-dependent Type II photosensitizers, Type I photosensitizers can produce a substantial amount of reactive oxygen species, even under hypoxic conditions, making them more suitable for photodynamic therapy of pancreatic cancer. However, the dense extracellular matrix of pancreatic cancer limits the penetration efficiency of photosensitizers, and the presence of immunosuppressive cells in the tumor microenvironment reduces the therapeutic effect. To address these challenges, we designed the photoimmunotherapeutic M1@PAP nanoparticles composed of Type I photosensitizer and anti-PD-L1 siRNA (siPD-L1), which was encapsulated into M1 macrophage membrane vesicles. In this system, pyropheophorbide-a (PPA) was covalently conjugated to poly-l-arginine (Arg9). Notably, it was capable of generating sufficient superoxide anions under hypoxic conditions, thereby functioning as a Type I photosensitizer. Furthermore, Arg9 acted as a nitric oxide (NO) donor, enhancing the penetration efficiency of the nanophotosensitizer by inhibiting cancer-associated fibroblast (CAF) activation and decomposing the tumor extracellular matrix. Additionally, M1 macrophage membrane vesicles provided active targeting capabilities and reeducated immunosuppressed M2 macrophages. The reversal of immunosuppressive microenvironment further promoted the efficacy of anti-PD-L1 siRNA immunotherapy, showing great potential in synergistic photodynamic immunotherapy against hypoxic pancreatic tumor.

The epithelial mesenchymal transition (EMT) is a biological process in which epithelial cells lose their polarity and adhesion characteristics, and adopt a mesenchymal phenotype. While the EMT naturally occurs during tissue fibrosis, wound healing, and embryonic development, it can be exploited by cancer cells and is strongly associated with cancer stem cell formation, tissue invasiveness, apoptosis, and therapy resistance. Transcription factors (TFs) such as SNAIL, ZEB, and TWIST play a pivotal role in driving the EMT. This systematic review aims to assess the impact of EMT-TFs on hematological malignancy and solid tumors.

English-language literature published between 2010 and 2024 was systematically reviewed, utilizing databases such as PubMed and Google Scholar.

A total of 3250 studies were extracted. Of these, 92 publications meeting the inclusion criteria were analyzed to elucidate the role of EMT-TFs in cancer. The results demonstrated that the EMT-TFs play a critical role in both hematological and solid tumor development and progression. They promote invasive, migratory, and metastatic properties in these tumors, and contribute to therapeutic challenges by enhancing chemoresistance. A strong correlation between EMT-TFs and poor overall survival has been identified.

Our research concluded that EMT-TFs may serve as important predictive and prognostic factors, as well as potential therapeutic targets to mitigate cancer progression.

The tumor microenvironment (TME) plays a crucial role in cancer progression and treatment response. It comprises a complex network of stromal cells, immune cells, extracellular matrix, and blood vessels, all of which interact with cancer cells and influence tumor behaviour. This review article provides an in-depth examination of the TME, focusing on stromal cells, blood vessels, signaling molecules, and ECM, along with commonly available therapeutic compounds that target these components. Moreover, we explore the TME as a novel strategy for discovering new anti-tumor drugs. The dynamic and adaptive nature of the TME offers opportunities for targeting specific cellular interactions and signaling pathways. We discuss emerging approaches, such as combination therapies that simultaneously target cancer cells and modulate the TME. Finally, we address the challenges and future prospects in targeting the TME. Overcoming drug resistance, improving drug delivery, and identifying new therapeutic targets within the TME are among the challenges discussed. We also highlight the potential of personalized medicine and the integration of emerging technologies, such as immunotherapy and nanotechnology, in TME-targeted therapies. This comprehensive review provides insights into the TME and its therapeutic implications. Understanding the TME's complexity and targeting its components offer promising avenues for the development of novel anti-tumor therapies and improved patient outcomes.

Pancreatic cancer is an aggressive tumor, which is often associated with a poor clinical prognosis and resistance to conventional chemotherapy. Therefore, there is a need to identify new therapeutic markers for pancreatic cancer. Although KIN17 is a highly expressed DNA‑ and RNA‑binding protein in a number of types of human cancer, its role in pancreatic cancer development, especially in relation to progression, is currently unknown. The present study verified the upregulation of KIN17 in pancreatic cancer using The Cancer Genome Atlas and Gene Expression Omnibus databases (GSE15471, GSE71989 and GSE62165), and identified an association between the PI3K/Akt/mTOR pathway and patient prognosis using publicly available datasets (Gene Expression Profiling Interactive Analysis). Immunohistochemistry was performed to determine the association between KIN17 and the pathological features of clinical pancreatic cancer samples. Furthermore, knockdown of KIN17 was shown to inhibit the migration and invasion of pancreatic cancer cells, and to reverse epithelial‑mesenchymal transition in pancreatic cancer cells through downregulation of Vimentin and N‑cadherin, and upregulation of E‑cadherin. Through various cellular experiments, the role of KIIN17 was explored in PI3K/AKT/mTOR activity. KIN17 inhibition was shown to suppress the migration and invasion of pancreatic cancer cells through PI3K/AKT/mTOR‑mediated autophagy. Furthermore, combined with mTOR inhibition, dual inhibition could enhance autophagy, leading to anti‑migratory and anti‑invasion effects in pancreatic cancer. In conclusion, the present study indicated that KIN17 may have a role in carcinogenesis and could serve as a prognostic biomarker of pancreatic cancer, owing to its high expression. In addition, KIN17 may be considered a potential therapeutic target with its knockdown having an inhibitory effect on pancreatic cancer.

Metabolic reprogramming shapes the tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. "Immune cold" PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of protumor macrophages, and reduced cytotoxic T cells in the TME. Analysis of fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in patients showed that increased global protein lactylation in PDAC correlates with worse clinical outcomes in immunotherapy. Inhibition of lactate production in pancreatic tumors via glycolysis or mutant-KRAS inhibition reshaped the TME, thereby increasing their sensitivity to immune checkpoint blockade (ICB) therapy. In pancreatic tumor cells, lactate induces K63 lactylation of endosulfine α (ENSA-K63la), a crucial step that triggers STAT3/CCL2 signaling. Consequently, elevated CCL2 secreted by tumor cells facilitates tumor-associated macrophage (TAM) recruitment to the TME. High levels of lactate also drive transcriptional reprogramming in TAMs via ENSA-STAT3 signaling, promoting an immunosuppressive environment. Targeting ENSA-K63la or CCL2 enhances the efficacy of ICB therapy in murine and humanized pancreatic tumor models. In conclusion, elevated lactylation reshapes the TME and promotes immunotherapy resistance in PDAC. A therapeutic approach targeting ENSA-K63la or CCL2 has shown promise in sensitizing pancreatic cancer immunotherapy.

Background: Amongst the various imaging techniques that provide surrogate tumor radiographic indications to aid in planning, monitoring, and predicting outcomes of therapy, ultrasound-guided photoacoustic imaging (US-PAI) is a promising non-ionizing modality based on endogenous blood (hemoglobin) and blood oxygen saturation (StO₂) contrast. Adaptation of US-PAI to the clinical realm requires macroscopic system configurations for adequate depth visualization. Methods: Here we present a vascular regional analysis (VRA) methodology of obtaining areas of low and high vessel density regions within the tumor (LVD and HVD respectively) by frequency domain filtering of macroscopic PA images. In this work, we evaluated the various vascular and oxygenation profiles of different murine xenografts of pancreatic cancer (AsPC-1, MIA PaCa-2, and BxPC-3) that have varying levels of angiogenic potentials and investigated the effects of receptor tyrosine kinase inhibitor (sunitinib) on the tumor microvessel density and StO₂. Results: The administration of sunitinib resulted in transient deoxygenation and reduction in vessel density within 72 h in two (AsPC-1 and MIA PaCa-2) of the three tumor types. Utilizing VRA, the regional change in StO2 (∆StO2) revealed the preferential targeting of sunitinib in LVD regions in only the AsPC-1 tumors. We also identified the presence of vascular normalization (validated through immunohistochemistry) in the sunitinib treated AsPC-1 tumors at day 8 post-treatment where a significant increases in HVD ∆StO2 (~20%) were seen following the 72-hour time point, indicative of improved vessel flow and functionality. Treated AsPC-1 vasculature displayed increased maturity and functionality compared to non-treated tumors on day 8, while these same metrics showed no conclusive evidence of vascular normalization in MIA PaCa-2 or BxPC-3 tumors. Conclusion: Overall, VRA as a tool to monitor treatment response allowed us to identify time points of vascular remodeling, highlighting its ability to provide insights into the tumor microenvironment for sunitinib treatment and other anti-angiogenic therapies.

Glutamine is the most abundant amino acid in human serum, and it can provide carbon and nitrogen for biosynthesis, which is crucial for proliferating cells. Moreover, it is widely known that glutamine metabolism is reprogrammed in cancer cells. Many cancer cells undergo metabolic reprogramming targeting glutamine, increasing its uptake to meet their rapid proliferation demands. An increasing amount of study is being done on the particular glutamine metabolic pathways in cancer cells.Further investigation into the function of glutamine in immune cells is warranted given the critical role these cells play in the fight against cancer. Immune cells use glutamine for a variety of biological purposes, including the growth, differentiation, and destruction of cancer cells. With the encouraging results of cancer immunotherapy in recent years, more investigation into the impact of glutamine metabolism on immune cell function in the cancer microenvironment could lead to the discovery of new targets and therapeutic approaches.Oral supplementation with glutamine also enhances the immune capabilities of cancer patients, improves the sensitivity to chemotherapy and radiotherapy, and improves prognosis. The unique metabolism of glutamine in cancer cells, its function in various immune cells, the impact of inhibitors of glutamine metabolism, and the therapeutic use of glutamine supplements are all covered in detail in this article.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors because of its high metastatic ability. The glutamine (Gln)-deficient microenvironment contributes to PDAC metastasis; however, the underlying molecular mechanisms remain unclear. Here, we demonstrated that melanophilin (MLPH) promotes PDAC metastasis by inducing the regrowth of primary cilia. Using RNA sequencing, we found that MLPH was upregulated in Gln-deficient conditions. MLPH facilitated PDAC metastasis in vitro and in vivo. Clinically, high MLPH expression is positively correlated with metastasis and poor PDAC prognosis. MLPH localized to the centrosome and facilitated the regrowth of primary cilia. The primary ciliogenesis upregulated phospholipase C γ-1 (PLCG1) to promote PDAC metastasis. Interestingly, PLCG1 was localized to the primary cilia, and depletion of PLCG1 alleviated primary ciliogenesis, suggesting a feedforward role for PLCG1 in mediating primary ciliogenesis. Thus, our study revealed a novel function of the MLPH-primary cilia-PLCG1 axis in facilitating PDAC metastasis under Gln deficiency both in vitro and in vivo.

Pancreatic cancer, referred to as the "monarch of malignancies," is a neoplastic growth mostly arising from the epithelial cells of the pancreatic duct and acinar cells. This particular neoplasm has a highly unfavorable prognosis due to its marked malignancy, inconspicuous initial manifestation, challenging early detection, rapid advancement, and limited survival duration. Cellular immunotherapy is the ex vivo culture and expansion of immune effector cells, granting them the capacity to selectively target malignant cells using specialized techniques. Subsequently, these modified cells are reintroduced into the patient's organism with the purpose of eradicating tumor cells and providing therapeutic intervention for cancer.

Presently, the primary cellular therapeutic modalities employed in the treatment of pancreatic cancer encompass CAR T-cell therapy, TCR T-cell therapy, NK-cell therapy, and CAR NK-cell therapy.

This review provides a concise overview of the mechanisms and primary targets associated with various cell therapies. Additionally, we will explore the prospective outlook of cell therapy in the context of treating pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of malignancies with worst outcomes among digestive system tumors. Identification of novel biomarkers is of great significance for treatment researches and prognosis prediction of pancreatic cancer patients. Due to OSBPL10 known involvement in oncogenic activity in other tumors, we elucidated the mechanism underlying its contribution to pancreatic cancer progression. We employed data from the Gene Expression Omnibus database to detect the expression of OSBPL10 in normal and pancreatic cancer tissues. A series of assays were conducted to assess the impact of OSBPL10 on the proliferation and metastatic capacities of pancreatic cancer cells and the influence of OSBPL10 on macrophages were evaluated by Flow cytometry. In addition, Co-immunoprecipitation, mass spectrometry, and western blot assays were utilized to investigate the potential mechanisms of OSBPL10 activity. From our study, OSBPL10 is revealed to be upregulated in pancreatic cancer, with poor prognosis. The overexpression promotes malignant behaviors of pancreatic cancer cells and has an impact on tumor immune microenvironment by stimulating the transformation M1 macrophages into M2 macrophages. Mechanistically, hypoxia induces the expression of OSBPL10 through interaction between hypoxia-inducible factor 1-α and the promoter region of OSBPL10. Additionally, OSBPL10 directly bound to CNBP, mediating CNBP expression and ultimately regulating the proliferation and metastasis capacity of pancreatic cancer cells, as well as influencing macrophage polarization. The research emphasized the oncogenic role of OSBPL10 in pancreatic cancer, uncovering key mechanisms involving hypoxia, HIF-1α, and CNBP. The finding suggests that OSBPL10 is a novel biomarker in pancreatic cancer, making it a potential therapeutic target for intervention in this malignancy.

Pancreas is a vital gland of gastrointestinal system with exocrine and endocrine secretory functions, interweaved into essential metabolic circuitries of the human body. Pancreatic ductal adenocarcinoma (PDAC) represents one of the most lethal malignancies, with a 5-year survival rate of 11%. This poor prognosis is primarily attributed to the absence of early symptoms, rapid metastatic dissemination, and the limited efficacy of current therapeutic interventions. Despite recent advancements in understanding the etiopathogenesis and treatment of PDAC, there remains a pressing need for improved individualized models, identification of novel molecular targets, and development of unbiased predictors of disease progression. Here we aim to explore the concept of precision medicine utilizing 3-dimensional, patient-specific cellular models of pancreatic tumors and discuss their potential applications in uncovering novel druggable molecular targets and predicting clinical parameters for individual patients.

N6-methyladenosine (m6A) is the most predominant RNA epigenetic regulation in eukaryotic cells. Numerous evidence revealed that m6A modification exerts a crucial role in the regulation of tumor microenvironment (TME) cell infiltration in several tumors. Nevertheless, the potential role and mechanism of m6A modification in nasopharyngeal carcinoma (NPC) remains unknown. mRNA expression data and clinical information from GSE102349, and GSE53819 datasets obtained from Gene Expression Omnibus (GEO) was used for differential gene expression and subsequent analysis. Consensus clustering was used to identify m6A-related molecular patterns of 88 NPC samples based on prognostic m6A regulators using Univariate Cox analysis. The TME cell-infiltrating characteristics of each m6A-related subclass were explored using single-sample gene set enrichment (ssGSEA) algorithm and CIBERSORT algotithm. DEGs between two m6A-related subclasses were screened using edgeR package. The prognostic signature and predicated nomogram were constructed based on the m6A-related DEGs. The cell infiltration and expression of prognostic signature in NPC was determined using immunohistochemistry (IHC) analysis. Chi-square test was used to analysis the significance of difference of the categorical variables. And survival analysis was performed using Kaplan-Meier plots and log-rank tests. The NPC samples were divided into two m6A-related subclasses. The TME cell-infiltrating characteristics analyses indicated that cluster 1 is characterized by immune-related and metabolism pathways activation, better response to anit-PD1 and anti-CTLA4 treatment and chemotherapy. And cluster 2 is characterized by stromal activation, low expression of HLA family and immune checkpoints, and a worse response to anti-PD1 and anti-CTLA4 treatment and chemotherapy. Furthermore, we identified 1558 DEGs between two m6A-related subclasses and constructed prognostic signatures to predicate the progression-free survival (PFS) for NPC patients. Compared to non-tumor samples, REEP2, TMSB15A, DSEL, and ID4 were upregulated in NPC samples. High expression of REEP2 and TMSB15A showed poor survival in NPC patients. The interaction between REEP2, TMSB15A, DSEL, ID4, and m6A regulators was detected. Our finding indicated that m6A modification plays an important role in the regulation of TME heterogeneity and complexity.

Immunotherapy has recently attracted considerable attention. However, currently, a thorough analysis of the trends associated with the epithelial-mesenchymal transition (EMT) and immunotherapy is lacking. In this study, we used bibliometric tools to provide a comprehensive overview of the progress in EMT-immunotherapy research. A total of 1,302 articles related to EMT and immunotherapy were retrieved from the Web of Science Core Collection (WOSCC). The analysis indicated that in terms of the volume of research, China was the most productive country (49.07%, 639), followed by the United States (16.89%, 220) and Italy (3.6%, 47). The United States was the most influential country according to the frequency of citations and citation burstiness. The results also suggested that Frontiers in Immunotherapy can be considered as the most influential journal with respect to the number of articles and impact factors. "Immune infiltration," "bioinformatics analysis," "traditional Chinese medicine," "gene signature," and "ferroptosis" were found to be emerging keywords in EMT-immunotherapy research. These findings point to potential new directions that can deepen our understanding of the mechanisms underlying the combined effects of immunotherapy and EMT and help develop strategies for improving immunotherapy.

The typical pathological feature of pancreatic ductal adenocarcinoma (PDAC) is a significant increase in stromal reaction, leading to a hypoxic and poorly vascularized tumor microenvironment. Tumor cells undergo metabolic reprogramming, such as the Warburg effect, yet the underlying mechanisms are not fully understood.

Interference and overexpression experiments were conducted to analyze the in vivo and in vitro effects of USP7 on the growth and glycolysis of tumor cells. Small-molecule inhibitors of USP7 and transgenic mouse models of PDAC were employed to assess the consequences of targeting USP7 in PDAC. The molecular mechanism underlying USP7-induced c-Myc stabilization was determined by RNA sequencing, co-IP and western blot analyses.

USP7 is abnormally overexpressed in PDAC and predicts a poor prognosis. Hypoxia and extracellular matrix stiffness can induce USP7 expression in PDAC cells. Genetic silencing of USP7 inhibits the glycolytic phenotypes in PDAC cells, while its overexpression has the opposite effect, as demonstrated by glucose uptake, lactate production, and extracellular acidification rate. Importantly, USP7 promotes PDAC tumor growth in a glycolysis-dependent manner. The small-molecule inhibitor P5091 targeting USP7 effectively suppresses the Warburg effect and cell growth in PDAC. In a transgenic mouse model of PDAC, named KPC, P5091 effectively blocks tumor progression. Mechanistically, USP7 interacts with c-Myc, enhancing its stability and expression, which in turn upregulates expression of glycolysis-related genes.

This study sheds light on the molecular mechanisms underlying the Warburg effect in PDAC and unveils USP7 as a potential therapeutic target for improving PDAC treatment.

Cancer drug resistance is a multifaceted phenomenon. The present review article aims to comprehensively analyze the cellular and molecular aspects of drug resistance in cancer and the strategies employed to overcome it.

A systematic search of relevant literature was conducted using electronic databases such as PubMed, Scopus, and Web of Science using appropriate key words. Original research articles and secondary literature were taken into consideration in reviewing the development in the field.

Cancer drug resistance is a pervasive challenge that causes many treatments to fail therapeutically. Despite notable advances in cancer treatment, resistance to traditional chemotherapeutic agents and novel targeted medications remains a formidable hurdle in cancer therapy leading to cancer relapse and mortality. Indeed, a majority of patients with metastatic cancer experience are compromised on treatment efficacy because of drug resistance. The multifaceted nature of drug resistance encompasses various factors, such as tumor heterogeneity, growth kinetics, immune system, microenvironment, physical barriers, and the emergence of undruggable cancer drivers. Additionally, alterations in drug influx/efflux transporters, DNA repair mechanisms, and apoptotic pathways further contribute to resistance, which may manifest as either innate or acquired traits, occurring prior to or following therapeutic intervention. Several strategies such as combination therapy, targeted therapy, development of P-gp inhibitors, PROTACs and epigenetic modulators are developed to overcome cancer drug resistance. The management of drug resistance is compounded by the patient and tumor heterogeneity coupled with cancer's ability to evade treatment. Gaining further insight into the mechanisms underlying medication resistance is imperative for the development of effective therapeutic interventions and improved patient outcomes.

Pancreatic ductal adenocarcinoma (PDAC) is one among the most lethal malignancies due to its aggressive behavior and resistance to conventional therapies. Hypoxia significantly contributes to cancer progression and therapeutic resistance of PDAC. microRNAs (miRNAs/miRs) have emerged as critical regulators of various biological processes. miR-210 is known as the "hypoxamir" due to its prominent role in cellular responses to hypoxia. In this study, we investigated the multifaceted role of miR-210 in PDAC using miR-210 knockout (KO) cellular models to elucidate its functions under hypoxic conditions. Hypoxia-inducible factor-1α (HIF1-α), a key transcription factor activated in response to low oxygen levels, upregulates miR-210. miR-210 maintains cancer stem cell (CSC) phenotypes and promotes epithelial-mesenchymal transition (EMT), which is essential for tumor initiation, metastasis, and therapeutic resistance. Our findings demonstrate that miR-210 regulates the expression of CSC markers, such as CD24, CD44, and CD133, and EMT markers, including E-cadherin, Vimentin, and Snail. Specifically, depletion of miR-210 reversed EMT and CSC marker expression levels in hypoxic Panc-1 and MiaPaCa-2 PDAC cells. These regulatory actions facilitate a more invasive and treatment-resistant PDAC phenotype. Understanding the regulatory network involving miR-210 under hypoxic conditions may reveal new therapeutic targets for combating PDAC and improving patient outcomes. Our data suggest that miR-210 is a critical regulator of HIF1-α expression, EMT, and the stemness of PDAC cells in hypoxic environments.

Tumor heterogeneity poses a significant challenge in cancer therapy. To address this, we analyze pharmacotherapeutic challenges by categorizing them into static and dynamic barriers, reframing these challenges to improve drug delivery, efficacy, and the development of controlled-release nanomedicines (CRNMs). This pathophysiology-driven approach facilitates the design of novel therapeutics tailored to overcome obstacles in pancreatic ductal adenocarcinoma (PDAC) using nanotechnology. Advanced biomaterials in nanodrug delivery systems offer innovative solutions by combining controlled release, stimuli sensitivity, and smart design strategies. CRNMs are engineered to modulate spatiotemporal signaling and control drug release in PDAC, where resistance to conventional therapies is particularly high. This review explores pharmacokinetic considerations for nanomedicine design, RNA interference (RNAi) for stromal modulation, and the development of targeted nanomedicine strategies. Additionally, we highlight the limitations of current animal models in capturing the complexities of PDAC and discuss notable clinical failures, such as PEGylated hyaluronidase (Phase III HALO 109-301 trial) and evofosfamide (TH-302) with gemcitabine (MAESTRO trial), underscoring the need for improved models and treatment strategies. By targeting pathways like Notch and Hedgehog and incorporating stimuli-sensitive and pathway-modulating agents, CRNMs offer a promising avenue to enhance drug penetration and efficacy, reshaping the paradigm of pancreatic cancer treatment.

Radiotherapy (RT) is a highly valuable method in cancer therapy, but its therapeutic efficacy is limited by its side effects and tumour radiation resistance. The resistance is mainly induced by hypoxia in the tumour microenvironment (TME). As a nano-oxygen carrier, Haemoglobin-based oxygen carriers (HBOCs) administration is a promising strategy to alleviate tumour hypoxia which may remodel TME to ameliorate radiation resistance and enable RT more effective. In this study, we administered fractionated RT combined with HBOC to treat Miapaca-2 cell and Hela cell xenografts on nude mice. The study found that HBOC relieved hypoxic environment and down-regulate expression of hypoxia-inducible factor-1α (Hif-1α) both in regular (100 mm3) and large (360/400 mm3) tumours. The proliferation and metastasis of tumour tissue also decreased after HBOC application. Nevertheless, in vivo RT combined with HBOC performed more effectively to suppress tumour growth in large tumours than in regular tumours. This is due to more severe hypoxic regions exist in the large solid tumours compared to the regular counterparts, and HBOC administration may be more effective in alleviating hypoxia in large tumours. Thus, HBOC sensitization therapy is more suitable for large solid tumours.

Pancreatic cancer (PC), a highly lethal tumor with nearly identical incidence and mortality rates, has become the sixth leading cause of cancer-related deaths. Hypoxia is an important malignant factor in PC, as it regulates angiogenesis, metabolic reprogramming, tumor progression, and metastasis. Disrupting the hypoxic microenvironment can enhance the efficacy of antitumor therapy and improve the prognosis of patients with PC. With the advent of bioinformatics, hypoxia-related PC models have emerged in recent years. They provide a reference for estimating the prognosis and immune microenvironment of patients with PC and identify potential biomarkers for targeting hypoxic microenvironment. However, these findings based on bioinformatic analysis may not be completely reliable without further experimental evidence and clinical cohort validation. The application of these models and biomarkers in clinical practice to predict survival time and develop anti hypoxic therapeutic strategies for patients with PC remains in its infancy. In this editorial, we review the current status of hypoxia-related prognostic models in PC, analyze their similarities and differences, discuss several existing challenges, and provide potential solutions and directions for further studies. This editorial will facilitate the optimization, validation, and determination of the molecular mechanisms of related models.

Osteosarcoma (OS) cells commonly suffer from hypoxia and dedifferentiation, resulting in poor prognosis. We plan to identify the role of hypoxia on dedifferentiation and the associated cellular signaling.

We performed sphere formation assays and determined spheroid cells as dedifferentiated cells by detecting stem cell-like markers. RNAi assay was used to explore the relationship between hypoxia inducible factor 1 subunit alpha (HIF1A) and platelet derived growth factor receptor beta (PDGFRB). We obtained PDGFRB knockdown and overexpression cells through lentiviral infection experiments and detected the expression of PDGFRB, p-PDGFRB, focal adhesion kinase (FAK), p-FAK, phosphorylated myosin light chain 2 (p-MLC2), and ras homolog family member A (RhoA) in each group. The effects of PDGFRB on cytoskeleton rearrangement and cell adhesion were explored by immunocytochemistry. Wound-healing experiments, transwell assays, and animal trials were employed to investigate the effect of PDGFRB on OS cell metastasis both in vitro and in vivo.

Dedifferentiated OS cells were found to exhibit high expression of HIF1A and PDGFRB, and HIF1A upregulated PDGFRB, subsequently activated RhoA, and increased the phosphorylation of MLC2. PDGFRB also enhanced the phosphorylation of FAK. The OS cell morphology and vinculin distribution were altered by PDGFRB. PDGFRB promoted cell dedifferentiation and had a significant impact on the migration and invasion abilities of OS cells in vitro. In addition, PDGFRB increased pulmonary metastasis of OS cells in vivo.

Our results demonstrated that HIF1A up-regulated PDGFRB under hypoxic conditions, and PDGFRB regulated the actin cytoskeleton, a process likely linked to the activation of RhoA and the phosphorylation of, thereby promoting OS dedifferentiation and pulmonary metastasis.

Limited oxygen (hypoxia) in solid tumors poses a challenge to successful immunotherapy with natural killer (NK) cells. NK cells have impaired cytotoxicity when cultured in hypoxia (1% oxygen) but not physiologic (>5%) or atmospheric oxygen (20%). We found that changes to cytotoxicity were regulated at the transcriptional level and accompanied by metabolic dysregulation. Dosing with interleukin-15 (IL-15) enhanced NK cell cytotoxicity in hypoxia, but preactivation with feeder cells bearing IL-21 and 4-1BBL was even better. Preactivation resulted in less perturbed metabolism in hypoxia; greater resistance to oxidative stress; and no hypoxia-induced loss of transcription factors (T-bet and Eomes), activating receptors, adhesion molecules (CD2), and cytotoxic proteins (TRAIL and FasL). There remained a deficit in CD122/IL-2Rβ when exposed to hypoxia, which affected IL-15 signaling. However, tri-specific killer engager molecules that deliver IL-15 in the context of anti-CD16/FcγRIII were able to bypass this deficit, enhancing cytotoxicity of both fresh and preactivated NK cells in hypoxia.

Associations between inflammation and cancer were first discovered approximately 160 years ago by Rudolf Virchow, who observed that tumors were infiltrated with inflammatory cells, and defined inflammation as a pathological condition. Inflammation has now emerged as one of the key mediators in oncogenesis and tumor progression, including pancreatic ductal adenocarcinoma (PDAC). However, the role of inflammatory processes in cancers is complicated and controversial, and the detailed regulatory mechanisms are still unclear. This review elucidates the dynamic interplay between inflammation and immune regulation, microenvironment alteration, metabolic reprogramming, and microbiome risk factors in PDAC, committing to exploring a deeper understanding of the role of crucial inflammatory pathways and molecules for providing insights into therapeutic strategies.