Pancreatic cancer is projected to become the second leading cause of cancer-related death by 2030. Conventional interventions including surgery, radiotherapy, and chemotherapy provide only modest survival benefits, underscoring an urgent need for more effective therapies. Although immunotherapy has revolutionized the management of several solid tumors, its clinical benefit in pancreatic cancer has so far been disappointing. Mounting evidence indicates that a highly immunosuppressive tumor microenvironment (TME), dominated by tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), drives immune evasion, tumor progression, metastasis, and chemoresistance through complex cytokine and chemokine networks. This review summarizes current knowledge of these immunosuppressive mechanisms and provides emerging strategies aimed at re-educating or depleting these cellular constituents to enhance the efficacy of immunotherapy in pancreatic cancer.

With fatal malignant peculiarities and poor survival rate, outcomes of pancreatic adenocarcinoma (PAAD) were frustrated by non-response and even resistance to therapy due to heterogeneity across clinical patients. Nevertheless, pharmacogenomics has been developed for individualized-treatment and still maintains obscure in PAAD.

A total of 964 samples from 10 independent multi-center cohorts were enrolled in our study. With drug response data from the profiling of relative inhibition simultaneously in mixtures (PRISM) and genomics of drug sensitivity in cancer (GDSC) databases, we established and validated multidimensionally three pharmacogenomics-classified subtypes using non-negative matrix factorization (NMF) and nearest template prediction (NTP) algorithms, separately. The heterogenous biological characteristics and precision medicine strategies among subtypes were further investigated.

Three pharmacogenomics-classified subtypes after stable and reproducible validation, distinguished in six aspects of prognosis, biological peculiarities, immune landscapes, genomic variations, immunotherapy and individualized management strategies. Subtype 2 was close to immunocompetent phenotype and projected to immunotherapy; Subtype 3 held most favorable outcomes and metabolic pathways distinctively, promising to be treated with first-line agents. Subtype 1 with worst prognosis, was anticipated to chromosome instability (CIN) phenotype and resistant to chemotherapeutic agents. In addition, ITGB6 contributed to subtype 1 resistance to 5-fluorouracil, and knockdown of ITGB6 enhanced sensitivity to 5-fluorouracil in in vitro experiments. Ultimately, appropriate clinical stratified treatments were assigned to corresponding subtypes according to pharmacogenomic transcripts. Some limitations were not taken into account, thus needs to be supported by more research.

A span-new molecular subtype exploited for PAAD uncovered an insight into precise medication on ground of pharmacogenomics, and highly refined multiple clinical management strategies for specific patients.

Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive and characterized by pronounced desmoplasia. PDAC cells communicate with cancer-associated fibroblasts (CAFs) in a paracrine/reciprocal manner, substantially promoting tumor growth and desmoplastic responses. This study highlights the critical role of anterior gradient 2 (AGR2), an endoplasmic reticulum protein disulfide isomerase, secreted by PDAC cells to activate CAFs via the Wnt signaling pathway. Activated CAFs, in turn, secrete insulin-like growth factor 1 (IGF1), which enhances AGR2 expression and secretion in PDAC cells through the IGF1 receptor (IGF1R)/c-JUN axis. Within PDAC cells, AGR2 acts as a thioredoxin, aiding the folding and cell surface presentation of IGF1R, essential for PDAC's response to CAF-derived IGF1. This reciprocal AGR2/IGF1 signaling loop intensifies desmoplasia, immunosuppression, and tumorigenesis, creating a harmful feedback loop. Targeting both pathways disrupts this interaction, reduces desmoplasia, and restores anti-tumor immunity in preclinical models, offering a promising therapeutic strategy against PDAC.

Peritoneal metastasis is the most common metastasis pattern of gastric cancer. Patients with gastric cancer peritoneal metastasis (GCPM) have a poor prognosis and respond poorly to conventional treatments. Recently, immune checkpoint blockade (ICB) has demonstrated favourable efficacy in the treatment of GCPM. Stratification of best responders and elucidation of resistance mechanisms of ICB therapies are highly important and remain major clinical challenges.

We performed a phase II trial involving patients with GCPM treated with ICB (sintilimab) combined with chemotherapy. The samples of primary tumours, GCPMs and peripheral blood from patients were collected for single-cell sequencing to comprehensively interpret the tumour microenvironment of GCPM and its impacts on immunotherapy efficacy.

The GCPM ecosystem coordinates a unique immunosuppressive pattern distinct from that of primary GC, which is dominated by a stroma-myeloid niche composed of SPP1+tumour-associated macrophages (TAMs) and Thrombospondin 2 (THBS2)+matrix cancer-associated fibroblasts (mCAFs). Consequently, this stroma-myeloid crosstalk is the major mediator of ICB resistance in patients with GCPM. Mechanistically, the accumulated THBS2+mCAFs facilitate the recruitment of peritoneum-specific tissue-resident macrophages and their transformation into SPP1+TAMs via the complement C3 and its receptor C3a receptor 1 (C3AR1), thereby forming a protumoral stroma-myeloid niche. Blocking the C3-C3AR1 axis disrupts the stroma-myeloid crosstalk and thereby significantly improves the benefits of ICB in in vivo models.

Our findings provide a new molecular portrait of cell compositions associated with ICB resistance in patients with GCPM and aid in the prioritisation of therapeutic candidates to potentiate immunotherapy.

The impact of endoplasmic reticulum (ER) stress in tumor-associated cells, such as cancer associated fibroblasts (CAFs), immune cells and endothelial cells, on patient outcomes in clinical specimens have not been examined. For the first time, we characterized the expression and spatial locations of ER stress markers, BiP and CHOP, in tumor-associated cells and assessed their prognostic significance in a panel of pancreatic ductal adenocarcinoma (PDAC) patient samples.

Multiplex immunofluorescence was performed on tumor microarrays and images were analyzed using HALO AI software.

BiP and CHOP were upregulated in CAFs and endothelial cells in PDAC sections relative to non-neoplastic pancreas sections. High BiP expression in CAFs and endothelial cells was associated with greater vascular invasion and in immune cells was correlated with increased tumor size. High CHOP expression in immune cells correlated with poor patient survival. CAFs and immune cells were more likely to express BiP or CHOP when located close (< 20 μm) to tumor cells. High expression of CHOP in CAFs close to tumor cells correlated with improved patient survival.

For the first time, this study demonstrated that ER stress occurs in CAFs and immune cells predominantly in proximity to tumor cells in PDAC patient tissue. The correlation of high ER stress in immune cells with poor patient survival highlights the importance of the TME and the use of spatial analysis for the identification of novel biomarkers.

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.

Recent developments in single-cell multi-omics technologies have provided the ability to identify diverse cell types and decipher key components of the tumor microenvironment (TME), leading to important advancements toward a much deeper understanding of how tumor microenvironment heterogeneity contributes to cancer progression and therapeutic resistance. These technologies are able to integrate data from molecular genomic, transcriptomic, proteomics, and metabolomics studies of cells at a single-cell resolution scale that give rise to the full cellular and molecular complexity in the TME. Understanding the complex and sometimes reciprocal relationships among cancer cells, CAFs, immune cells, and ECs has led to novel insights into their immense heterogeneity in functions, which can have important consequences on tumor behavior. In-depth studies have uncovered immune evasion mechanisms, including the exhaustion of T cells and metabolic reprogramming in response to hypoxia from cancer cells. Single-cell multi-omics also revealed resistance mechanisms, such as stromal cell-secreted factors and physical barriers in the extracellular matrix. Future studies examining specific metabolic pathways and targeting approaches to reduce the heterogeneity in the TME will likely lead to better outcomes with immunotherapies, drug delivery, etc., for cancer treatments. Future studies will incorporate multi-omics data, spatial relationships in tumor micro-environments, and their translation into personalized cancer therapies. This review emphasizes how single-cell multi-omics can provide insights into the cellular and molecular heterogeneity of the TME, revealing immune evasion mechanisms, metabolic reprogramming, and stromal cell influences. These insights aim to guide the development of personalized and targeted cancer therapies, highlighting the role of TME diversity in shaping tumor behavior and treatment outcomes.

Within the intricate milieu of colorectal cancer (CRC) tissues, cancer-associated fibroblasts (CAFs) act as pivotal orchestrators, wielding considerable influence over tumor progression. This review endeavors to dissect the multifaceted functions of CAFs within the realm of CRC, thereby highlighting their indispensability in fostering CRC malignant microenvironment and indicating the development of CAFs-targeted therapeutic interventions. Through a comprehensive synthesis of current knowledge, this review delineates insights into CAFs-mediated modulation of cancer cell proliferation, invasiveness, immune evasion, and neovascularization, elucidating the intricate web of interactions that sustain the pro-tumor metabolism and secretion of multiple factors. Additionally, recognizing the high level of heterogeneity within CAFs is crucial, as they encompass a range of subtypes, including myofibroblastic CAFs, inflammatory CAFs, antigen-presenting CAFs, and vessel-associated CAFs. Innovatively, the symbiotic relationship between CAFs and the intestinal microbiota is explored, shedding light on a novel dimension of CRC pathogenesis. Despite remarkable progress, the orchestrated dynamic functions of CAFs remain incompletely deciphered, underscoring the need for continued research endeavors for therapeutic advancements in CRC management.

Chemotherapy resistance is the main reason of treatment failure in gastric cancer (GC). However, the mechanism of oxaliplatin (OXA) resistance remains unclear. Here, we demonstrate that extracellular mechanical signaling plays crucial roles in OXA resistance within GC. We selected OXA-resistant GC patients and analyzed tumor tissues by single-cell sequencing, and found that the mitochondrial content of GC cells increased in a biosynthesis-independent manner. Moreover, we found that the increased mitochondria of GC cells were mainly derived from mesenchymal stromal cells (MSCs), which could repair the mitochondrial function and reduce the levels of mitophagy in GC cells, thus leading to OXA resistance. Furthermore, we investigated the underlying mechanism and found that mitochondrial transfer was mediated by mechanical signals of the extracellular matrix (ECM). After OXA administration, GC cells actively secreted ECM in the tumor microenvironment (TEM), increasing matrix stiffness of the tumor tissues, which promoted mitochondria to transfer from MSCs to GC cells via microvesicles (MVs). Meanwhile, inhibiting the mechanical-related RhoA/ROCK1 pathway could alleviate OXA resistance in GC cells. In summary, these results indicate that matrix stiffness could be used as an indicator to identify chemotherapy resistance, and targeting mechanical-related pathway could effectively alleviate OXA resistance and improve therapeutic efficacy.

A distinct feature of pancreatic ductal adenocarcinoma (PDAC) is a prominent tumor microenvironment (TME) with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance. The dynamic crosstalk between cancer cells and the dense stromal compartment leads to spatially and temporally heterogeneous metabolic alterations, such as acidic pH that contributes to drug resistance in PDAC. Thus, monitoring the extracellular pH metabolic fluctuations within the TME is crucial to predict and to quantify anticancer drug efficacy. Here, a simple and reliable alginate-based 3D PDAC model embedding ratiometric optical pH sensors and cocultures of tumor (AsPC-1) and stromal cells for simultaneously monitoring metabolic pH variations and quantify drug response is presented. By means of time-lapse confocal laser scanning microscopy (CLSM) coupled with a fully automated computational analysis, the extracellular pH metabolic variations are monitored and quantified over time during drug testing with gemcitabine, folfirinox, and paclitaxel, commonly used in PDAC therapy. In particular, the extracellular acidification is more pronounced after drugs treatment, resulting in increased antitumor effect correlated with apoptotic cell death. These findings highlight the importance of studying the influence of cellular metabolic mechanisms on tumor response to therapy in 3D tumor models, this being crucial for the development of personalized medicine approaches.

Pancreatic adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer deaths by 2030 and this is mostly due to therapy failure. Limited treatment options and resistance to standard-of-care (SoC) therapies makes PDAC one of the cancer types with poorest prognosis and survival rates [1,2]. Pancreatic tumors are renowned for their poor response to therapeutic interventions including targeted therapies, chemotherapy and radiotherapy. Herein, we review hallmarks of therapy resistance in PDAC and current strategies aiming to tackle escape mechanisms and to re-sensitize cancer cells to therapy. We will further provide insights on recent advances in the field of drug discovery, nanomedicine, and disease models that are setting the ground for future research.

Insulin-like growth factors (IGFs) are crucial for embryonic and postnatal growth and development, influencing cell survival, metabolism, myogenesis, and cancer progression. Many studies have demonstrated that IGFs also play prominent roles in the modulation of both innate and adaptive immune systems during inflammation. Strikingly, IGFs dictate the phenotype and functional properties of macrophages and T cells. Furthermore, the interplay between IGFs and inflammatory cytokines may generate tissue-protective properties during inflammation. Herein, we review the recent advances on the dialogue between immune cells and IGFs, especially zooming in on the significance of immunomodulatory properties in inflammatory conditions, cancer and autoimmune diseases. The investigation of IGFs may have broad clinical implications.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with an urgent unmet clinical need for new therapies. Using a combination of in vitro assays and in vivo preclinical models we demonstrate that therapeutic inhibition of the IGF signalling axis promotes the accumulation of CD8+ cytotoxic T cells within the tumour microenvironment of PDAC tumours. Mechanistically, we show that IGF blockade promotes macrophage and fibroblast production of the chemokines CXCL9 and CXCL10 to facilitate CD8+ T cell recruitment and trafficking towards the PDAC tumour. Exploring this pathway further, we show that IGF inhibition leads to increased STAT1 transcriptional activity, correlating with a downregulation of the AKT/STAT3 signalling axis, in turn promoting Cxcl9 and Cxcl10 gene transcription. Using patient derived tumour explants, we also demonstrate that our findings translate into the human setting. PDAC tumours are frequently described as "immunologically cold", therefore bolstering CD8+ T cell recruitment to PDAC tumours through IGF inhibition may serve to improve the efficacy of immune checkpoint inhibitors which rely on the presence of CD8+ T cells in tumours.

Pancreatic ductal adenocarcinoma (PDAC) is a challenge for global health with very low survival rate and high therapeutic resistance. Hence, advanced preclinical models for treatment screening are of paramount importance. Herein, chemotherapeutic (gemcitabine) assessment on novel (polyurethane) scaffold-based spatially advanced 3D multicellular PDAC models is carried out. Through comprehensive image-based analysis at the protein level, and expression analysis at the mRNA level, the importance of stromal cells is confirmed, primarily activated stellate cells in the chemoresistance of PDAC cells within the models. Furthermore, it is demonstrated that, in addition to the presence of activated stellate cells, the spatial architecture of the scaffolds, i.e., segregation/compartmentalization of the cancer and stromal zones, affect the cellular evolution and is necessary for the development of chemoresistance. These results highlight that, further to multicellularity, mapping the tumor structure/architecture and zonal complexity in 3D cancer models is important for better mimicry of the in vivo therapeutic response.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most recalcitrant cancers due to its late diagnosis, poor therapeutic response, and highly heterogeneous microenvironment. Nanotechnology has the potential to overcome some of the challenges to improve diagnostics and tumor-specific drug delivery but they have not been plausibly viable in clinical settings. The review focuses on active targeting strategies to enhance pancreatic tumor-specific uptake for nanoparticles. Additionally, this review highlights using actively targeted liposomes, micelles, gold nanoparticles, silica nanoparticles, and iron oxide nanoparticles to improve pancreatic tumor targeting. Active targeting of nanoparticles toward either differentially expressed receptors or PDAC tumor microenvironment (TME) using peptides, antibodies, small molecules, polysaccharides, and hormones has been presented. We focus on microenvironment-based hallmarks of PDAC and the potential for actively targeted nanoparticles to overcome the challenges presented in PDAC. It describes the use of nanoparticles as contrast agents for improved diagnosis and the delivery of chemotherapeutic agents that target various aspects within the TME of PDAC. Additionally, we review emerging nano-contrast agents detected using imaging-based technologies and the role of nanoparticles in energy-based treatments of PDAC. This article is categorized under: Implantable Materials and Surgical Technologies > Nanoscale Tools and Techniques in Surgery Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Drug delivery is a key component of nanomedicine, and conventional delivery relies on the adsorption or encapsulation of drug molecules to a nanomaterial. Many delivery vehicles contain metal ions, such as metal-organic frameworks, metal oxides, transition metal dichalcogenides, MXene, and noble metal nanoparticles. These materials have a high metal content and pose potential long-term toxicity concerns leading to difficulties for clinical approval. In this review, recent developments are summarized in the use of drug molecules as ligands for metal coordination forming various nanomaterials and soft materials. In these cases, the drug-to-metal ratio is much higher than conventional adsorption-based strategies. The drug molecules are divided into small-molecule drugs, nucleic acids, and proteins. The formed hybrid materials mainly include nanoparticles and hydrogels, upon which targeting ligands can be grafted to improve efficacy and further decrease toxicity. The application of these materials for addressing cancer, viral infection, bacterial infection inflammatory bowel disease, and bone diseases is reviewed. In the end, some future directions are discussed from fundamental research, materials science, and medicine.

To elucidate the currently unknown molecular mechanisms responsible for the similarity and difference during the acquirement of resistance against gemcitabine (GEM) and paclitaxel (PTX) in patients with pancreatic carcinoma, we examined two-dimensional (2D) and three-dimensional (3D) cultures of parent MIA PaCa-2 cells (MIA PaCa-2-PA) and their GEM resistance cell line (MIA PaCa-2-GR) and PTX resistance (MIA PaCa-2-PR). Using these cells, we examined 3D spheroid configurations and cellular metabolism, including mitochondrial and glycolytic functions, with a Seahorse bio-analyzer and RNA sequencing analysis. Compared to the MIA PaCa-2-PA, (1) the formation of the 3D spheroids of MIA PaCa-2-GR or -PR was much slower, and (2) their mitochondrial and glycolytic functions were greatly modulated in MIA PaCa-2-GR or -PR, and such metabolic changes were also different between their 2D and 3D culture conditions. RNA sequencing and bioinformatic analyses of the differentially expressed genes (DEGs) using an ingenuity pathway analysis (IPA) suggested that various modulatory factors related to epithelial -mesenchymal transition (EMT) including STAT3, GLI1, ZNF367, NKX3-2, ZIC2, IFIT2, HEY1 and FBLX, may be the possible upstream regulators and/or causal network master regulators responsible for the acquirement of drug resistance in MIA PaCa-2-GR and -PR. In addition, among the prominently altered DEGs (Log2 fold changes more than 6 or less than -6), FABP5, IQSEC3, and GASK1B were identified as unique genes associated with their antisense RNA or pseudogenes, and among these, FABP5 and GASK1B are known to function as modulators of cancerous EMT. Therefore, the observations reported herein suggest that modulations of cancerous EMT may be key molecular mechanisms that are responsible for inducing chemoresistance against GEM or PTX in MIA PaCa-2 cells.

Tumor-infiltrating CD8 + T cells play a key role in glioblastoma (GB) development, malignant progression, and recurrence. The aim of the study was to establish nomograms based on the Visually AcceSAble Rembrandt Images (VASARI) features of multiparametric magnetic resonance imaging (MRI) to determine the expression levels of tumor-infiltrating CD8 + T cells in patients with GB.

Pathological and imaging data of 140 patients with GB confirmed by surgery and pathology were retrospectively analyzed. The levels of tumor-infiltrating CD8 + T cells in tumor tissue samples obtained from patients were quantified using immunohistochemical staining. Patients were divided into high and low CD8 expression groups. The MRI images of patients with GB were analyzed by two radiologists using the VASARI scoring system.

A total of 25 MRI-based VASARI imaging features were evaluated by two neuroradiologists. The features with the greatest predictive power for CD8 expression levels were, cystic (OR, 3.063; 95% CI: 1.387, 6.766; P = 0.006), hemorrhage (OR, 2.980; 95% CI: 1.172, 7.575; P = 0.022), and ependymal extension (OR, 0.257; 95% CI: 0.114 0.581; P = 0.001). A logistic regression model based on these three features showed better sample predictive performance (AUC=0.745; 95% CI: 0.665, 0.825; Sensitivity=0.527; Specificity=0.857).

The VASARI feature-based nomogram model can show promise to predict the level of infiltrative CD8 expression in GB tumors non-invasively for earlier tissue diagnosis and more aggressive treatment.

The tumor microenvironment (TME) significantly influences prognosis and drug resistance in various tumors, yet its heterogeneity and the mechanisms affecting therapeutic response remain unclear in gastric cancer (GC).

The heterogenous TME were explored with single-cell RNA-sequencing (scRNA-seq) data of 50 primary GC samples. We then identified four GC TME subtypes with nonnegative matrix factorization (NMF) and constructed a pearson nearest-centroid classifier based on subtype-specific upregulated genes. Genomic features and clinical significance of four subtypes were comprehensively evaluated. We reclustered fibroblasts to identify cancer-associated fibroblast (CAF) subtype associated with poor clinical outcomes. RT-qPCR and double immunofluorescence staining were applied to validate the findings. Cellchat analysis elucidated potential molecular mechanisms of the CAF subtype in GC disease progression and chemotherapy resistance.

The GC TME exhibited high heterogeneity, influencing chemo-sensitivity. Four TME-based subtypes predicting response to immunotherapy and chemotherapy were identified and validated in 1406 GC patients. Among which, ISG1 subtype displayed higher fibroblasts infiltration and heightened oncogenic pathways, and inferior response to chemotherapy with unfavorable prognosis. Microsatellite instability-high (MSI-H) GCs within four TME subtypes showed immunological heterogeneity. We then reported an IGF1-overexpressing CAF was associated with chemo-resistance and GC recurrence. Cell communication analysis revealed IGF1+ CAF may induce drug-resistant phenotypes in tumor cells through IGF1-α6β4 integrin ligand-receptor binding and activation of EMT biological process.

We identified four TME-based subtypes with different clinical outcomes and IGF1+ CAFs contributing to poor clinical outcomes in GC, which might provide guidance for individualized treatment and facilitate the development of novel therapeutic targets.

Currently, pancreatic cancer (PC) is one of the most lethal malignant tumors. PC is typically diagnosed at a late stage, exhibits a poor response to conventional treatment, and has a bleak prognosis. Unfortunately, PC's survival rate has not significantly improved since the 1960s. Cancer-associated fibroblasts (CAFs) are a key component of the pancreatic tumor microenvironment (TME). They play a vital role in maintaining the extracellular matrix and facilitating the intricate communication between cancer cells and infiltrated immune cells. Exploring therapeutic approaches targeting CAFs may reverse the current landscape of PC therapy. In recent years, nano-drug delivery systems have evolved rapidly and have been able to accurately target and precisely release drugs with little or no toxicity to the whole body. In this review, we will comprehensively discuss the origin, heterogeneity, potential targets, and recent advances in the nano-drug delivery system of CAFs in PC. We will also propose a novel integrated treatment regimen that utilizes a nano-drug delivery system to target CAFs in PC, combined with radiotherapy and immunotherapy. Additionally, we will address the challenges that this regimen currently faces.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease, yet effective treatments to inhibit PDAC metastasis are lacking. The rich PDAC tumor microenvironment plays a major role in disease progression. Macrophages are the most abundant immune cell population in PDAC tumors and can acquire a range of functions that either hinder or promote tumor growth and metastasis. Here, we identified that mesothelin secretion by pancreatic cancer cells co-opts macrophages to support tumor growth and metastasis of cancer cells to the lungs, liver, and lymph nodes. Mechanistically, secretion of high levels of mesothelin by metastatic cancer cells induced the expression of VEGF alpha (VEGFA) and S100A9 in macrophages. Macrophage-derived VEGFA fed back to cancer cells to support tumor growth, and S100A9 increased neutrophil lung infiltration and formation of neutrophil extracellular traps. These results reveal a role for mesothelin in regulating macrophage functions and interaction with neutrophils to support PDAC metastasis.

Mesothelin secretion by cancer cells supports pancreatic cancer metastasis by inducing macrophage secretion of VEGFA and S100A9 to support cancer cell proliferation and survival, recruit neutrophils, and stimulate neutrophil extracellular trap formation. See related commentary by Alewine, p. 513.

Tumor drug resistance emerges from the interaction of two critical factors: tumor cellular heterogeneity and the immunosuppressive nature of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) constitute essential components of the TME. M2-like TAMs are essential in facilitating tumor metastasis as well as augmenting the drug resistance of tumors. This review encapsulates the mechanisms that M2-like TAMs use to promote tumor drug resistance. We also describe the emerging therapeutic strategies that are currently targeting M2-like TAMs in combination with other antitumor drugs, with some still undergoing clinical trial evaluation. Furthermore, we summarize and analyze various existing approaches for developing novel drugs that target M2-like TAMs to overcome tumor resistance, highlighting how targeting M2-like TAMs can effectively stop tumor growth, metastasis, and overcome tumor drug resistance.

Cancer-associated fibroblasts (CAFs) are an abundant component of the tumor microenvironment and have been shown to possess critical functions in tumor progression. Although their roles predominantly have been described as tumor-promoting, more recent findings have identified subsets of CAFs with tumor-restraining functions. Accumulating evidence underscores large heterogeneity in fibroblast subsets in which distinct subsets differentially impact the initiation, progression, and metastasis of colorectal cancer. In this review, we summarize and discuss the evolving role of CAFs in colorectal cancer, highlighting the ongoing controversies regarding their distinct origins and multifaceted functions. In addition, we explore how CAFs can confer resistance to current therapies and the challenges of developing effective CAF-directed therapies. Taken together, we believe that, in this rapidly evolving field, it is crucial first to understand CAF dynamics comprehensively, and to bridge existing knowledge gaps regarding CAF heterogeneity and plasticity before further exploring the clinical targeting of CAFs.

Gastrointestinal cancers (GICs) are one of the most recurrent diseases in the world. Among all GICs, pancreatic cancer (PC) is one of the deadliest and continues to disrupt people's lives worldwide. The most frequent pancreatic cancer type is pancreatic ductal adenocarcinoma (PDAC), representing 90 to 95% of all pancreatic malignancies. PC is one of the cancers with the worst prognoses due to its non-specific symptoms that lead to a late diagnosis, but also due to the high resistance it develops to anticancer drugs. Gemcitabine is a standard treatment option for PDAC, however, resistance to this anticancer drug develops very fast. The microbiome was recently classified as a cancer hallmark and has emerged in several studies detailing how it promotes drug resistance. However, this area of study still has seen very little development, and more answers will help in developing personalized medicine. PC is one of the cancers with the highest mortality rates; therefore, it is crucial to explore how the microbiome may mold the response to reference drugs used in PDAC, such as gemcitabine. In this article, we provide a review of what has already been investigated regarding the impact that the microbiome has on the development of PDAC in terms of its effect on the gemcitabine pathway, which may influence the response to gemcitabine. Therapeutic advances in this type of GIC could bring innovative solutions and more effective therapeutic strategies for other types of GIC, such as colorectal cancer (CRC), due to its close relation with the microbiome.

We assessed the safety and efficacy of an EGFR-targeted, super-cytotoxic drug, PNU-159682-packaged nanocells with α-galactosyl ceramide-packaged nanocells (E-EDV-D682/GC) in patients with advanced pancreatic ductal adenocarcinoma (PDAC) who had exhausted all treatment options.

ENG9 was a first-in-man, single-arm, open-label, phase I/IIa, dose-escalation clinical trial. Eligible patients had advanced PDAC, Eastern Cooperative Oncology Group status 0 to 1, and failed all treatments. Primary endpoints were safety and overall survival (OS).

Of 25 enrolled patients, seven were withdrawn due to rapidly progressive disease and one patient withdrew consent. All 25 patients were assessed for toxicity, 24 patients were assessed for OS, which was also assessed for 17 patients completing one treatment cycle [evaluable subset (ES)]. Nineteen patients (76.0%) experienced at least one treatment-related adverse event (graded 1 to 2) resolving within hours. There were no safety concerns, dose reductions, patient withdrawal, or treatment-related deaths.

Median OS (mOS) was 4.4 months; however, mOS of the 17 ES patients was 6.9 months [208 days; range, 83-591 days; 95.0% confidence interval (CI), 5.6-10.3 months] and mOS of seven patients who did not complete one cycle was 1.8 months (54 days; range, 21-72; 95.0% CI, 1.2-2.2 months). Of the ES, 47.1% achieved stable disease and one partial response. Ten subjects in the ES survived over 6 months, the longest 19.7 months. During treatments, 82.0% of the ES maintained stable weight.

E-EDV-D682/GC provided significant OS, minimal side effects, and weight stabilization in patients with advanced PDAC. Advanced PDAC can be safely treated with super-cytotoxic drugs via EnGeneIC Dream Vectors to overcome multidrug resistance.

Conventional cancer treatments face the challenge of therapeutic resistance, which causes poor treatment outcomes. The use of combination therapies can improve treatment results in patients and is one of the solutions to overcome this challenge. Chemotherapy is one of the conventional treatments that, due to the non-targeted and lack of specificity in targeting cancer cells, can cause serious complications in the short and long-term for patients by damaging healthy cells. Also, the employment of a wide range of strategies for chemotherapy resistance by cancer cells, metastasis, and cancer recurrence create serious problems to achieve the desired results of chemotherapy. Accordingly, targeted therapies can be used as a combination treatment with chemotherapy to both cause less damage to healthy cells, which as a result, they reduce the side effects of chemotherapy, and by targeting the factors that cause therapeutic challenges, can improve the results of chemotherapy in patients.

Small molecules are one of the main targeted therapies that can be used for diverse targets in cancer treatment due to their penetration ability and characteristics. However, small molecules in cancer treatment are facing obstacles that a better understanding of cancer biology, as well as the mechanisms and factors involved in chemotherapy resistance, can lead to the improvement of this type of major targeted therapy.

In this review article, at first, the challenges that lead to not achieving the desired results in chemotherapy and how cancer cells can be resistant to chemotherapy are examined, and at the end, research areas are suggested that more focusing on them, can lead to the improvement of the results of using targeted small molecules as an adjunctive treatment for chemotherapy in the conditions of chemotherapy resistance and metastasis of cancer cells.

Pancreatic cancer is the seventh leading cause of cancer-related deaths, and chemotherapy is one of the most important treatments for pancreatic cancer. Unfortunately, pancreatic cancer cells can block chemotherapy drugs from entering the tumor. This is owing to interactions between the tumor's environment and the cancer cells. Here, we review the latest research on the mechanisms by which pancreatic cancer cells block the chemotherapy drug, gemcitabine. The results of our review can help identify potential therapeutic targets for the blocking of gemcitabine by pancreatic cancer cells and may provide new strategies to help chemotherapy drugs penetrate tumors.

Tumor-associated macrophages (TAMs), as a major and essential component of tumor microenvironment (TME), play a critical role in orchestrating pancreatic cancer (PaC) tumorigenesis from initiation to angiogenesis, growth, and systemic dissemination, as well as immunosuppression and resistance to chemotherapy and immunotherapy; however, the critical intrinsic factors responsible for TAMs reprograming and function remain to be identified. By performing single-cell RNA sequencing, transforming growth factor-beta-induced protein (TGFBI) was identified as TAM-producing factor in murine PaC tumors. TAMs express TGFBI in human PaC and TGFBI expression is positively related with human PaC growth. By inducing TGFBI loss-of-function in macrophage (MΦs) in vitro with siRNA and in vivo with Cre-Lox strategy in our developed TGFBI-floxed mice, we demonstrated disruption of TGFBI not only inhibited MΦ polarization to M2 phenotype and MΦ-mediated stimulation on PaC growth, but also significantly improved anti-tumor immunity, sensitizing PaC to chemotherapy in association with regulation of fibronectin 1, Cxcl10, and Ccl5. Our studies suggest that targeting TGFBI in MΦ can develop an effective therapeutic intervention for highly lethal PaC.

Gastrointestinal cancers are highly aggressive malignancies with significant mortality rates. Recent research emphasizes the critical role of the tumor microenvironment (TME) in these cancers, which includes cancer-associated fibroblasts (CAFs), a key component of the TME that have diverse origins, including fibroblasts, mesenchymal stem cells, and endothelial cells. Several markers, such as α-SMA and FAP, have been identified to label CAFs, and some specific markers may serve as potential therapeutic targets. In this review article, we summarize the literature on the multifaceted role of CAFs in tumor progression, including their effects on angiogenesis, immune suppression, invasion, and metastasis. In addition, we highlight the use of single-cell transcriptomics to understand CAF heterogeneity and their interactions within the TME. Moreover, we discuss the dynamic interplay between CAFs and the immune system, which contributes to immunosuppression in the TME, and the potential for CAF-targeted therapies and combination approaches with immunotherapy to improve cancer treatment outcomes.

Despite continuous improvements in research and new cancer therapeutics, the goal of eradicating cancer remains elusive because of drug resistance. For a long time, drug resistance research has been focused on tumor cells themselves; however, recent studies have found that the tumor microenvironment also plays an important role in inducing drug resistance. Cancer-associated fibroblasts (CAFs) are a main component of the tumor microenvironment. They cross-talk with cancer cells to support their survival in the presence of anticancer drugs. This review summarizes the current knowledge of the role of CAFs in tumor drug resistance. An in-depth understanding of the mechanisms underlying the cross-talk between CAFs and cancer cells and insight into the importance of CAFs in drug resistance can guide the development of new anticancer strategies.

Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all major cancers. Chemotherapy is the mainstay systemic therapy for PDAC, and chemoresistance is a major clinical problem leading to therapeutic failure. This study aimed to identify key differences in gene expression profile in tumors from chemoresponsive and chemoresistant patients.

Archived formalin-fixed paraffin-embedded tumor tissue samples from patients treated with neoadjuvant chemotherapy were obtained during surgical resection. Specimens were macrodissected and gene expression analysis was performed. Multi- and univariate statistical analysis was performed to identify differential gene expression profile of tumors from good (0%-30% residual viable tumor [RVT]) and poor (>30% RVT) chemotherapy-responders.

Initially, unsupervised multivariate modeling was performed by principal component analysis, which demonstrated a distinct gene expression profile between good- and poor-chemotherapy responders. There were 396 genes that were significantly (p < 0.05) downregulated (200 genes) or upregulated (196 genes) in tumors from good responders compared to poor responders. Further supervised multivariate analysis of significant genes by partial least square (PLS) demonstrated a highly distinct gene expression profile between good- and poor responders. A gene biomarker of panel (IL18, SPA17, CD58, PTTG1, MTBP, ABL1, SFRP1, CHRDL1, IGF1, and CFD) was selected based on PLS model, and univariate regression analysis of individual genes was performed. The identified biomarker panel demonstrated a very high ability to diagnose good-responding PDAC patients (AUROC: 0.977, sensitivity: 82.4%; specificity: 87.0%).

A distinct tumor biological profile between PDAC patients who either respond or not respond to chemotherapy was identified.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid malignancies, with a five-year survival of less than 10%. The resistance of the disease and the associated lack of therapeutic response is attributed primarily to its dense, fibrotic stroma, which acts as a barrier to drug perfusion and permits tumour survival and invasion. As clinical trials of chemotherapy (CT), radiotherapy (RT), and targeted agents have not been successful, improving the survival rate in unresectable PDAC remains an urgent clinical need. Photodynamic stromal depletion (PSD) is a recent approach that uses visible or near-infrared light to destroy the desmoplastic tissue. Preclinical evidence suggests this can resensitise tumour cells to subsequent therapies whilst averting the tumorigenic effects of tumour-stromal cell interactions. So far, the pre-clinical studies have suggested that PDT can successfully mediate the destruction of various stromal elements without increasing the aggressiveness of the tumour. However, the complexity of this interplay, including the combined tumour promoting and suppressing effects, poses unknowns for the clinical application of photodynamic stromal depletion in PDAC.

Pancreatic ductal adenocarcinoma (PDA) is a pernicious disease characterized by an immunosuppressive milieu that is unresponsive to current immunotherapies. Interleukin-1 receptor antagonist (IL-1Ra) is a natural anti-inflammatory cytokine; however, its contribution to cancer pathogenesis and immunosuppression remains elusive. In this research, we investigated the role and mechanism of IL-1Ra in malignant progression of PDA.

Through analyzing clinical dataset and examining the pathological tumor tissues and serum samples, we have demonstrated that IL-1Ra expression is elevated in human PDA and positively associated with malignant progression of PDA. To study the biological function of IL-1Ra in tumors, we generated a set of mouse pancreatic cancer cell lines with a knockout (KO) of the Il1rn gene, encoding IL-1Ra, and compared the tumor growth rates in immune-competent and immune-deficient mice. We found that the Il1rn KO cells exhibited greater tumor inhibition in immune-competent mice, highlighting the crucial role of a functional immune system in Il1rn KO-mediated anti-tumor response. Consistently, we found an increase in CD8+ T cells and a decrease in CD11b+Ly6G- immunosuppressive mononuclear population in the tumor microenvironment of Il1rn KO-derived tumors. To monitor the inhibitory effects of IL-1Ra on immune cells, we utilized a luciferase-based reporter CD4+ T cell line and splenocytes, which were derived from transgenic mice expressing ovalbumin-specific T cell receptors in CD8+ T cells, and mice immunized with ovalbumin. We showed that IL-1Ra suppressed T cell receptor signaling and inhibited antigen-specific interferon-γ (IFN-γ) secretion and cytolytic activity in splenocytes.

Our findings illustrate the immunosuppressive properties of the natural anti-inflammatory cytokine IL-1Ra, and provide a rationale for considering IL-1Ra-targeted therapies in the treatment of PDA.

Cuproptosis is a novel cell death pathway, and the regulatory mechanism in pancreatic cancer (PC) is unclear. The authors aimed to figure out whether cuproptosis-related lncRNAs (CRLs) could predict prognosis in PC and the underlying mechanism. First, the prognostic model based on seven CRLs screened by the least absolute shrinkage and selection operator Cox analysis was constructed. Following this, the risk score was calculated for pancreatic cancer patients and divided patients into high and low-risk groups. In our prognostic model, PC patients with higher risk scores had poorer outcomes. Based on several prognostic features, a predictive nomogram was established. Furthermore, the functional enrichment analysis of differentially expressed genes between risk groups was performed, indicating that endocrine and metabolic pathways were potential regulatory pathways between risk groups. TP53, KRAS, CDKN2A, and SMAD4 were dominant mutated genes in the high-risk group and tumour mutational burden was positively correlated with the risk score. Finally, the tumour immune landscape indicated patients in the high-risk group were more immunosuppressive than that in the low-risk group, with lower infiltration of CD8+ T cells and higher M2 macrophages. Above all, CRLs can be applied to predict PC prognosis, which is closely correlated with the tumour metabolism and immune microenvironment.