Metabolic reprogramming characterized by mitochondrial dysfunction and increased glycolysis is associated with aggressive tumor biology and poor therapeutic response. The interplays among NADPH oxidase (NOX)-mediated reactive oxygen species, regulation of glycolysis and oxidative phosphorylation (OXPHOS) in cancer cells suggest an opportunity to develop a new cancer therapy. We found that treatment with a hyaluronic acid nanoparticle encapsulated with GKT831 (HANP/GKT831), a NOX1/4 inhibitor, markedly inhibited the proliferation and invasion of cancer cells. Treated tumor cells had reduced levels of mitochondrial ROS, glycolysis, and OXPHOS. The combination of HANP/GKT831 with radiation reduced colony formation and invasion of tumor cells. The combination therapy markedly inhibited the levels of molecules in glycolysis, OXPHOS, and DNA repairing pathways in tumor cells. Systemic administrations of HANP/GKT831 combined with radiotherapy significantly inhibited tumor growth by 84.7 % in a mouse colorectal tumor model. Tumors treated with HANP/GKT831 and radiation had increased DNA damage and apoptotic cell death. Furthermore, the combined therapy increased intratumoral infiltration of activated cytotoxic T cells and M1 macrophages but reduced the levels of immunosuppressive fibroblasts and M2 macrophages. Our results support HANP/GKT831 as a cancer nanotherapeutic agent that induces redox and bioenergy stresses in cancer cells for enhanced therapeutic response to radiotherapy.

Glutamine (Gln), a critical metabolic substrate, fuels the uncontrolled proliferation of cancer cells. Cancer-associated fibroblasts (CAFs), essential components of the tumor microenvironment, facilitate tumor progression by supplying Gln to cancer cells and driving drug resistance through metabolic reprogramming. This review highlights the key processes of Gln uptake, transport, and catabolism and explores the metabolic crosstalk between CAFs and cancer cells. It also examines the roles of major oncogenic regulators-c-Myc, mTORC, KRAS, p53, and HIF-in controlling Gln metabolism and shaping therapeutic resistance. Current pharmacological approaches targeting Gln metabolism, including enzyme inhibitors and transporter blockers, are discussed alongside emerging therapeutic strategies and ongoing clinical trials. Lastly, we underscore the importance of integrating advanced technologies like artificial intelligence and spatial omics to refine treatment targeting and develop more effective, personalized therapeutic interventions.

Metabolic reprogramming is a defining feature of pancreatic cancer, influencing tumor progression and the tumor microenvironment. By integrating single-cell transcriptomics, spatial transcriptomics, and spatial metabolomics, this study visualized the spatial co-localization of metabolites and gene expression within tumor samples, uncovering metabolic heterogeneity and intercellular interactions. Spatial transcriptomics identified distinct pathological regions, which were further characterized using single-cell transcriptomic data and pathologist annotations. Pseudotime trajectory analysis revealed metabolic shifts along the malignant progression, while single-cell Metabolism (scMetabolism) delineated metabolic differences between pathological regions, classifying them as hypermetabolic or hypometabolic. Notably, aberrant cell communication between cancer cells, macrophages, and fibroblasts was observed, with key receptor-ligand pairs significantly co-expressed in malignant regions and correlated with poor prognosis. Spatial metabolomics imaging identified signature metabolites, highlighting metabolic alterations in amino acid metabolism, polyamine metabolism, fatty acid synthesis, and phospholipid metabolism. This integrated analysis provides critical insights into pancreatic cancer metabolism, offering potential avenues for targeted therapeutic interventions.

Myosins, a superfamily of actin-based molecular motor proteins, are important regulators of actin cytoskeleton structure and remodeling. They act as mechano-sensors of the tumor environment, controlling key cellular processes associated with tumorigenesis and mediating various cellular activities, including muscle contraction, cell migration, intracellular transport, membrane protrusion formation, cell adhesion, and cell signaling. In eukaryotic cells, autophagy plays a crucial role in maintaining cellular homeostasis by transporting cytoplasmic cargo to lysosomes for selective degradation. In tumors, recent research has explored the function of the role of myosin-influenced autophagy and tumor microenvironment-associated immune cells. Increasing evidence exists on how myosins and their mediated autophagy-related processes affect cancer development and progression. In this review, we discuss and dissect the functions played by different myosins at various stages of autophagy, and how myosins mediate autophagy involvement in the tumor process, based on the summaries of these findings, we provide new perspectives for possible therapeutic strategies.

Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism1,2. For example, PDAC uses, and is dependent on, high levels of autophagy and other lysosomal processes3-5. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the difficulty in identifying and characterizing favourable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase that is integral to lysosomal functioning7, as a targetable vulnerability in PDAC. Using a genetically engineered mouse model, we established that PIKfyve is essential to PDAC progression. Furthermore, through comprehensive metabolic analyses, we found that PIKfyve inhibition forces PDAC to upregulate a distinct transcriptional and metabolic program favouring de novo lipid synthesis. In PDAC, the KRAS-MAPK signalling pathway is a primary driver of de novo lipid synthesis. Accordingly, simultaneously targeting PIKfyve and KRAS-MAPK resulted in the elimination of the tumour burden in numerous preclinical human and mouse models. Taken together, these studies indicate that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a dire prognosis. Standard-of-care chemotherapy regimens offer marginal survival benefit and carry risk of severe toxicity, while immunotherapy approaches have uniformly failed in clinical trials. Extensive desmoplasia in the PDAC tumor microenvironment (TME) disrupts blood flow to and from the tumor, thereby creating a nutrient-depleted, hypoxic, and acidic milieu that suppresses the function of antitumor immune cells and imparts chemotherapy resistance. Additionally, recent seminal studies have demonstrated crucial roles for metabolic crosstalk - the exchange of metabolites between PDAC cells and stromal cell populations in the TME - in establishing and maintaining core malignant behaviors of PDAC: tumor growth, metastasis, immune evasion, and therapy resistance. In this review, we provide a conceptual overview of metabolic crosstalk and how it evolves under various selection pressures in the TME, analyze the landscape of proposed tumorigenic metabolic crosstalk pathways, and highlight potentially druggable nodes.

Extracellular proteins like transforming growth factor-β (TGFβ) are crucial enforcers in the development of cancer stroma and the tumor immunosuppressive microenvironment. Lysosome-targeting chimera-mediated protein degradation appeared as a promising tool for extracellular signal interference but was limited by several lysosome-trafficking receptors and inadequate in vivo degradation efficiency. Here, we designed a multivalent aptamer assembly with a universal pattern to drag extracellular proteins (e.g., TGFβ1) for lysosome degradation with high tumor specificity. By accelerating cell recognition-internalization and lysosomal delivery, the assembly promoted TGFβ blockade and degradation in pancreatic cancer cells and pancreatic stellate cells (PSCs). In vivo, the assembly exhibited highly tumor-specific accumulation and prolonged retention, which resulted in efficient TGFβ inhibition, stromal remodeling, and reversed polarization of immunosuppressive cells in the tumor microenvironment, as well as synergic therapeutic effects when combined with gemcitabine or ovalbumin. Therefore, this study provides a feasible strategy to construct a multivalent aptamer assembly for tumor-specific extracellular protein degradation, after remodeling the tumor stromal and immunosuppressive microenvironment in a manner that enhances the effects of cancer chemotherapy and immunotherapy.

The tumor microenvironment (TME) influences cancer cell metabolism and survival. However, how immune and stromal cells respond to metabolic stress in vivo, and how nutrient limitations affect therapy, remains poorly understood. Here, we introduce Dual Ribosome Profiling (DualRP) to simultaneously monitor translation and ribosome stalling in multiple tumor cell populations. DualRP reveals that cancer-fibroblast interactions trigger an inflammatory program that reduces amino acid shortages during glucose starvation. In immunocompetent mice, we show that serine and glycine are essential for optimal T cell function and that their deficiency impairs T cell fitness. Importantly, immune checkpoint blockade therapy imposes amino acid restrictions specifically in T cells, demonstrating that therapies create distinct metabolic demands across TME cell types. By mapping codon-resolved ribosome stalling in a cell‑type‑specific manner, DualRP uncovers metabolic crosstalk that shapes translational programs. DualRP thus offers a powerful, innovative approach for dissecting tumor cell metabolic interplay and guiding combined metabolic-immunotherapeutic strategies.

Autophagy is a conserved catabolic process that is essential for maintaining cellular homeostasis by degrading and recycling damaged organelles and misfolded proteins. In cancer, autophagy exhibits a context-dependent dual role: In early stages, autophagy acts as a tumor suppressor by preserving genomic integrity and limiting oxidative stress. In advanced stages, autophagy supports tumor progression by facilitating metabolic adaptation, therapy resistance, immune evasion, and metastasis. This review highlights the molecular mechanisms underlying this dual function and focuses on the transcriptional and epigenetic regulation of autophagy in cancer cells. Key transcription factors, including the MiT/TFE family, FOXO family, and p53, as well as additional regulators, are discussed in the context of stress-responsive pathways mediated by mTORC1 and AMPK. A deeper understanding of the transcriptional and epigenetic regulation of autophagy in cancer is crucial for developing context-specific therapeutic strategies to either promote or inhibit autophagy depending on the cancer stage, thereby improving clinical outcomes in cancer treatment.

The stroma of healthy pancreases contains various non-hematopoietic, non-endothelial mesenchymal cells. It is altered by chronic inflammation which in turn is a major contributor to the development of pancreatic adenocarcinoma (PDAC). In PDAC, the stroma plays a decisive and well-investigated role for tumor progression and therapy response. This review addresses the central role of stromal cells in the early inflammation-driven development of PDAC. It focuses on major subpopulations of pancreatic mesenchymal cells, i.e., fibroblasts, pancreatic stellate cells, and multipotent stroma cells, particularly their activation and functional alterations upon chronic inflammation including the development of different types of carcinoma-associated fibroblasts. In the second part, the current knowledge on the impact of activated stroma cells on acinar-to-ductal metaplasia and the transition to pancreatic intraepithelial neoplasia is summarized. Finally, putative strategies to target stroma cells and their signaling in early pancreatic carcinogenesis are reflected. In summary, the current data show that the activation of pancreatic stroma cells and the resulting fibrotic changes has pro- and anti-carcinogenetic effects but, overall, creates a carcinogenesis-promoting microenvironment. However, this is a dynamic process and the therapeutic targeting of specific pathways and cells requires in-depth knowledge of the molecular interplay of various cell types.

Tumor metastasis represents a stepwise progression and stands as a principal determinant of unfavorable prognoses among cancer patients. Consequently, an in-depth exploration of its mechanisms holds paramount clinical significance. Cancer-associated fibroblasts (CAFs), constituting the most abundant stromal cell population within the tumor microenvironment (TME), have garnered robust evidence support for their pivotal regulatory roles in tumor metastasis.

This review systematically explores the roles of CAFs at eight critical stages of tumorigenic dissemination: 1) extracellular matrix (ECM) remodeling, 2) epithelial-mesenchymal transition (EMT), 3) angiogenesis, 4) tumor metabolism, 5) perivascular migration, 6) immune escape, 7) dormancy, and 8) premetastatic niche (PMN) formation. Additionally, we provide a compendium of extant strategies aimed at targeting CAFs in cancer therapy.

This review delineates a structured framework for the interplay between CAFs and tumor metastasis while furnishing insights for the potential therapeutic developments. It contributes to a deeper understanding of cancer metastasis within the TME, facilitating the utilization of CAF-targeting therapies in anti-metastatic approaches.

The cellular metabolism undergoes reprogramming during the metastatic process. We hypothesised that serum metabolites at the time of primary tumour diagnosis might identify rectal cancer patients prone to metastatic progression.

One hundred twenty-three rectal cancer patients from a prospective observational biomarker study were followed up to 5 years after study entry. We have assessed metabolites in serum sampled at the time of diagnosis by 1H-nuclear magnetic resonance spectroscopy, using the internal reference trimethylsilylpropanoic acid for quantification.

Here we show that patients who develop overt metastatic disease more than 6 months after the primary tumour diagnosis have elevated serum levels (Kruskal-Wallis test) of alanine (P = 0.005), lactate (P = 0.023), pyruvate (P = 0.041) and citrate (P = 0.007) compared to those without metastases at the 5-year follow-up or with metastases already 6 months or sooner after the cancer diagnosis. Patients with serum citrate above 0.24 mmol/L have poorer progression-free survival compared to those with levels below (P < 0.001; log-rank test).

We observe a distinct serum metabolite profile, in particular involving citrate to the best of our knowledge shown for the first time clinically, in rectal cancer patients at heightened risk of metastasis already when the primary tumour is diagnosed, offering insights into the metabolism of metastatic progression.

Aberrant expression of the phosphatase SHP2 is implicated in numerous cancers, including KRAS G12D mutation driven PDAC. Although several SHP2 inhibitors have been reported, specific inhibitors with potent efficacy are not yet available. Given the elevated autophagy in PDAC, herein, we first designed novel SHP2 degraders through autophagosome-tethering compound strategy. Among them, the preferred 11n formed hydrogen bonds with Arg 111 and Glu 250 residues of SHP2 to enhance interactions between SHP2 and LC3. 11n also possessed great efficacy and selectivity against KRAS G12D mutant cancer cells versus the wild type. Moreover, the degradation caused by 11n manipulated the signaling pathways associated with cell apoptosis, metastasis, and invasion to inhibit the tumor growth both in vitro and in vivo. These findings not only generated a useful tool for exploring the potential of targeting SHP2 degradation but also offered promising candidates to develop novel drugs based on the autophagy mechanism.

Pancreatic ductal adenocarcinoma (PDAC) is characterised by early metastasis and resistance to anti-cancer therapy, leading to an overall poor prognosis. Macroautophagy (hereinafter referred to as autophagy) is a conserved cellular homeostasis mechanism that degrades various cargoes (e.g., proteins, organelles, and pathogens) mainly playing a role in promoting survival under environmental stress. Autophagy is an essential defense mechanism against PDAC initiation, acting on multiple levels to maintain cellular and tissue homeostasis. However, autophagy is also intimately involved in the molecular mechanisms driving PDAC progression, facilitating the adaptation of cancer cells to the tumor microenvironment's harsh conditions. In this review, we examine the complex role of autophagy in PDAC and assess the potential of modulating autophagy as a therapeutic strategy. By reviewing current research and clinical trials, we seek to elucidate how targeting autophagy can disrupt PDAC tumor survival mechanisms, enhance the efficacy of existing treatments, and ultimately improve patient outcomes.

The tumor microenvironment (TME) plays a critical role in the poor clinical outlook for pancreatic ductal adenocarcinoma (PDAC). Activated pancreatic stellate cells (PSC) drive the complex interactions within the TME, resulting in a microenvironment that is resistant to chemotherapy and tolerant to the immune system, thereby promoting tumor growth. Effective deactivation of PSC is vital in treating pancreatic cancer. However, previous studies have only focused on limited changes in PSC phenotype without comprehensively analysing their overall function. Our transcriptome analysis identified agents capable of modulating multiple biological functions of PSC, including fibrosis, extracellular matrix generation, and the secretion of cytokines and immune factors. Through this comprehensive assessment, we discovered that flumethasone (Flu) effectively deactivates PSC. This glucocorticoid analogue remodels the tumor microenvironment by regulating the secretomes of PSC and their interaction with tumor cells. Additionally, our research revealed that activated PSC exhibited heightened albumin endocytosis. As a result, we propose that albumin conjugation could serve as an effective targeted drug delivery approach for PSC. Our findings also demonstrate that albumin-conjugated Flu maintained reprogramming capabilities in stromal cells, and enhanced the efficacy of chemotherapy in orthotopic mouse models of PDAC and KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) pancreatic tumor allograft mouse model. Our investigation into the mechanism of PSC deactivation by flumethasone has revealed its potential for clinical cancer treatment through its effects on the tumor microenvironment. Furthermore, the conjugation of flumethasone to albumin enhances its safety and targeted delivery, offering a promising approach for PSC-targeted drug application in pancreatic cancer treatment.

The tumor microenvironment (TME) of gliomas comprises glioma cells and surrounding cells, such as astrocytes, macrophages, T cells, and neurons. In the TME, glioma cells can activate normal human astrocytes (NHAs) through the secretion of exosomes and the activation of astrocytes can further improve the progression of glioma, leading to a poor prognosis for patients. However, the molecular mechanisms underlying NHAs activation by gliomas remain largely unknown. It this study, glioma-derived exosomes (GDEs) play an important role in the modulation of autophagy and activation of NHAs. Compared with normoxic GDEs, hypoxic glioma-derived exosomes (H-GDEs) further improved autophagy and activation of astrocytes, which strongly promoted the progression of glioma cells. In an miRNA array between two types of exosomes from gliomas, miR-423-3p was highly expressed in H-GDEs and played an important role in autophagy, resulting in the activation of NHAs. The mechanism by which hypoxic glioma cells react with NHAs to create an immunosuppressive microenvironment was identified and 15d-PGJ2 was established as an effective inhibitor of miR-423-3p to suppress NHAs activation. These findings provide new insights into the diagnosis and treatment of gliomas by targeting autophagy and miR-423-3p expression.

Primary central nervous system lymphoma (PCNSL) is a rare and highly aggressive form of non-Hodgkin lymphoma, primarily confined to the central nervous system. In recent years, growing evidence has indicated that dysbiosis of the gut microbiota is closely associated with the development of various malignancies. This study aims to systematically explore the potential role of gut microbiota and their metabolic pathways in the pathogenesis of PCNSL by integrating metagenomic and metabolomic approaches.

A total of 33 PCNSL patients and 32 healthy controls were enrolled in this study, and fecal samples were collected from each participant. The fecal samples were analyzed using metagenomic and metabolomic techniques, followed by KEGG pathway enrichment analysis to investigate the biological pathways enriched by the differential gut microbiota and metabolites.

Significant differences were observed in the composition of gut microbiota and metabolites between PCNSL patients and healthy controls. In the gut microbiota of PCNSL patients, the abundance of the phylum Proteobacteria was markedly increased, while the Firmicutes/Bacteroidetes (F/B) ratio was significantly elevated. Metabolomic analysis revealed that the abundance of oleamide was significantly reduced in the PCNSL group, while the relative abundance of deoxycholic acid was significantly elevated. KEGG pathway analysis indicated that the differential gut microbiota and metabolites were primarily involved in key metabolic pathways such as nitrogen metabolism, phenylalanine metabolism, purine metabolism, and pyrimidine metabolism, with these pathways being more active in PCNSL patients.

This study is the first to systematically investigate the differences in gut microbiota and their metabolites between PCNSL patients and healthy individuals, highlighting the potential role of gut microbiota alterations in the pathogenesis of PCNSL.

Extensive fibrous stroma plays an important role in gemcitabine (GEM) resistance. However, the mechanism by which pancreatic cancer cells interact with pancreatic stellate cells (PSCs) to promote GEM resistance remains unclear. This study investigates the role of metabolic crosstalk between these two cells in inducing GEM resistance. Extracellular vesicles (EVs) of parental and GEM-resistant pancreatic cancer cells are extracted and performed metabolic assays and long noncoding RNA (lncRNA) sequencing. Pancreatic cancer cell-derived EVs promote PSCs activation and extracellular matrix formation, and GEM-resistant pancreatic cancer cells produce more asparagine (Asn), favoring PSCs activation. Mechanistically, pancreatic cancer cell-derived EVs mediate linc-ZNF25-1 to promote Asn uptake via the IGF2BP3/c-Myc/SLC1A5 pathway in PSCs. In addition, mouse models elucidate the oncogenic function of linc-ZNF25-1 and the enhanced therapeutic effect of asparaginase (L-ASNase) in combination with GEM in pancreatic cancer. This study demonstrates that pancreatic cancer cell-derived EVs promote the uptake of Asn released from pancreatic cancer cells through the upregulation of SLC1A5 in PSCs, facilitating PSCs activation and pancreatic cancer resistance to GEM. L-ASNase in combination with GEM is a potential therapeutic strategy for targeting stromal cells to enhance the efficacy of chemotherapeutic agents against pancreatic cancer.

Metabolic reprogramming of cancer cells and the tumour microenvironment are pivotal characteristics of cancers, and studying these processes offer insights and avenues for cancer diagnostics and therapeutics. Recent advancements have underscored the impact of host systemic features, termed macroenvironment, on facilitating cancer progression. During tumorigenesis, these inherent features of the host, such as germline genetics, immune profile and the metabolic status, influence how the body responds to cancer. In parallel, as cancer grows, it induces systemic effects beyond the primary tumour site and affects the macroenvironment, for example, through inflammation, the metabolic end-stage syndrome of cachexia, and metabolic dysregulation. Therefore, understanding the intricate metabolic interplay between the tumour and the host is a growing frontier in advancing cancer diagnosis and therapy. In this Review, we explore the specific contribution of the metabolic fitness of the host to cancer initiation, progression and response to therapy. We then delineate the complex metabolic crosstalk between the tumour, the microenvironment and the host, which promotes disease progression to metastasis and cachexia. The metabolic relationships among the host, cancer pathogenesis and the consequent responsive systemic manifestations during cancer progression provide new perspectives for mechanistic cancer therapy and improved management of patients with cancer.

Alterations in amine metabolite levels are closely associated with the poor progression of pancreatic disease, including acute pancreatitis (AP) and pancreatic cancer (PC). However, effectively quantifying and visualizing these metabolites through mass spectrometry (MS) has proven to be challenging. Here, we have designed a novel and rapid strategy for analyzing the amine submetabolome within liquid chromatography-mass spectrometry (LC-MS) and air-flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) platforms by inducing a pair of isotope-labeling-based photochemical derivatization reagents. The simultaneous introduction of a 4-amino-1-methylpyridinium moiety renders a 160- to 1037-fold higher response in MS. Coupled with full MS-ddMS2 and precursor ion scan modes, this labeling strategy allows for straightforward detection of 423 peaks for indazolone derivatives and identification of 82 amine metabolites in biological samples. The semiquantitation of the 82 amines in plasma from AP patients and healthy controls resulted in the discovery of unreported aromatic amines and aminoaldehydes with significant changes in AP and employing ethanolamine for distinguishing the severities of AP in the early stage. In the MSI platform, the photochemical reagent can efficiently derivatize primary amine metabolites avoiding spatial deviation and significantly enhancing imaging sensitivity in rat brain and kidney. Further joint analysis of amine submetabolome in plasma and pancreas from PC patients by use of these two platforms allowed for identifying the significant metabolite, methylamine. These results together enhance the role of amine-driven biomarker discovery in the diagnosis of pancreatic disease and accelerate the application of on-tissue photochemical derivation in MSI.

Cancer dormancy is a phenomenon defined by the entry of cancer cells into a reversible quiescent, nonproliferative state, and represents an essential part of the metastatic cascade responsible for cancer recurrence and mortality. Emerging evidence suggests that metabolic reprogramming plays a pivotal role in enabling entry, maintenance, and exit from dormancy in the face of the different environments of the metastatic cascade. Here, we review the current literature to understand the dynamics of metabolism during dormancy, highlighting its fine-tuning by the host micro- and macroenvironment, and put forward the importance of identifying metabolic vulnerabilities of the dormant state as therapeutic targets to eradicate recurrent disease.

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.

Cancer-associated fibroblasts (CAFs) and immune cells make up two major components of the tumor microenvironment (TME), contributing to an ecosystem that can either support or restrain cancer progression. Metabolism is a key regulator of the TME, providing a means for cells to communicate with and influence each other, modulating tumor progression and anti-tumor immunity. Cells of the TME can metabolically interact directly through metabolite secretion and consumption or by influencing other aspects of the TME that, in turn, stimulate metabolic rewiring in target cells. Recent advances in understanding the subtypes and plasticity of cells in the TME both open up new avenues and create challenges for metabolically targeting the TME to hamper tumor growth and improve response to therapy. This perspective explores ways in which the CAF and immune components of the TME could metabolically influence each other, based on current knowledge of their metabolic states, interactions, and subpopulations.

Background/Objectives: Endoplasmic reticulum (ER) stress occurs when ER homeostasis is disrupted, leading to the accumulation of misfolded or unfolded proteins. This condition activates the unfolded protein response (UPR), which aims to restore balance or trigger cell death if homeostasis cannot be achieved. In cancer, ER stress plays a key role due to the heightened metabolic demands of tumor cells. This review explores how metabolomics can provide insights into ER stress-related metabolic alterations and their implications for cancer therapy. Methods: A comprehensive literature review was conducted to analyze recent findings on ER stress, metabolomics, and cancer metabolism. Studies examining metabolic profiling of cancer cells under ER stress conditions were selected, with a focus on identifying potential biomarkers and therapeutic targets. Results: Metabolomic studies highlight significant shifts in lipid metabolism, protein synthesis, and oxidative stress management in response to ER stress. These metabolic alterations are crucial for tumor adaptation and survival. Additionally, targeting ER stress-related metabolic pathways has shown potential in preclinical models, suggesting new therapeutic strategies. Conclusions: Understanding the metabolic impact of ER stress in cancer provides valuable opportunities for drug development. Metabolomics-based approaches may help identify novel biomarkers and therapeutic targets, enhancing the effectiveness of antitumor therapies.

The tumor microenvironment is a dynamic and complex three-dimensional network comprising the extracellular matrix and diverse non-cancerous cells, including fibroblasts, adipocytes, endothelial cells and various immune cells (lymphocytes T and B, NK cells, dendritic cells, monocytes/macrophages, myeloid-derived suppressor cells, and innate lymphoid cells). A constantly and rapidly growing number of studies highlight the critical role of these cells in shaping cancer survival, metastatic potential and therapy resistance. This review provides a synthesis of current knowledge on the modulating role of the cellular microenvironment in cancer progression and response to treatment.

The extracellular matrix (ECM) is the common denominator of more than 50 chronic diseases. Some of these chronic pathologies lead to enhanced tissue formation and deposition, whereas others are associated with increased tissue degradation, and some exhibit a combination of both, leading to severe tissue alterations. To develop effective therapies for diseases affecting the lung, liver, kidney, skin, intestine, musculoskeletal system, heart, and solid tumors, we need to modulate the ECM's composition to restore its organization and function. Across diverse organ diseases, there are common denominators and distinguishing factors in this fibroinflammatory axis, which may be used to foster new insights into drug development across disease indications. The 2nd Extracellular Matrix Pharmacology Congress took place in Copenhagen, Denmark, from 17 to 19 June 2024 and was hosted by the International Society of Extracellular Matrix Pharmacology. The event was attended by 450 participants from 35 countries, among whom were prominent scientists who brought together state-of-the-art research on organ diseases and asked important questions to facilitate drug development. We highlight key aspects of the ECM in the liver, kidney, skin, intestine, musculoskeletal system, lungs, and solid tumors to advance our understanding of the ECM and its central targets in drug development. We also highlight key advances in the tools and technology that enable this drug development, thereby supporting the ECM.

Gemcitabine combined with albumin-paclitaxel (AG) is a crucial therapeutic option for pancreatic ductal adenocarcinoma (PDAC). However, the response to chemotherapy is relatively poor, with rapid development of resistance. The aim of this study was to explore the mechanism of resistance to AG and to develop strategies that can sensitize the AG regimen.

We used organoid models, patient-derived xenografts, and genetically engineered mouse models in our study. Chromatin immunoprecipitation, double luciferase assay, co-immunoprecipitation, and far-western blotting analysis were performed to investigate the mechanism. The AVL9 inhibitors were identified through protein structure analysis and molecular docking analysis, and their efficacy was verified in patient-derived xenografts, patient-derived organoids-based xenograft, and KPC models.

Through multistrategy screening, we identified AVL9 as a key target for AG resistance in PDAC. Its tumor-promoting effects were confirmed in our clinical cohorts. Mechanistically, HIF-1α, a hypoxia-related transcription factor, drives the expression of AVL9. AVL9 acts as a scaffold that facilitates the binding of IκBα to SKP1, leading to enhanced ubiquitination and degradation of IκBα, which further activates the nuclear factor-κB pathway. The potential AVL9-targeting inhibitor, Edotecarin, was shown to reverse AG chemo-resistance in PDAC.

AVL9 expression is driven by HIF-1α in PDAC. The physical interaction of AVL9, IκBα, and SKP1 provides a novel molecular mechanism for the abnormal activation of the nuclear factor-κB pathway. Therefore, the AVL9-targeting drug Edotecarin could be a promising therapeutic strategy for sensitizing PDAC to AG.

The tumor microenvironment (TME) has been linked with the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer. A central component of the TME are cancer-associated fibroblasts (CAFs), which can either suppress or promote tumor growth in a context-dependent manner. In this review, we will discuss the multi-faceted roles of CAFs in tumor-stroma interactions influencing cancer initiation, progression and therapeutic response.

Ovarian cancer is one of most common gynaecologic malignancy and ranks third in cancer-related deaths among women. Ursolic acid (UA) is a pharmacologically active pentacyclic triterpenoid isolated from a large variety of vegetables, fruits and many traditional medicinal plants. However, the mechanism of action of UA in inhibiting the proliferation of ovarian cancer cells remains unclear. Consequently, this experiment was designed to elucidate the mechanism of action of UA in inhibiting the proliferation of ovarian cancer cells in greater detail.The results indicated that UA was capable of effectively inhibiting the proliferation, migration, and colony formation of ovarian cancer cells.UA was observed to up-regulate Bcl-2-associated X protein(BAX)and cysteinyl aspartate specific proteinase 3 (Caspase3) expression and down-regulating B-cell lymphoma-2(Bcl-2) expression.Meanwhile, UA up-regulated Sequestosome 1(p62)expression and down-regulated coiled-coil, moesin-like BCL2-interacting protein(Becline1), microtubule-associated proteins light chain 3(LC3), Phosphoinositide 3-Kinase(PI3K), andProtein Kinase B( AKT) expression, thus effectively inhibiting autophagy in ovarian cancer cells.Furthermore, UA upregulated pancreatic ER kinase (PKR)-like ER kinase (PERK), eukaryotic translation initiation factor 2 A(eIF2α), and The C/EBP Homologous Protein(CHOP) expression.In addition UA upregulates PERK, eIF2α, and CHOP expression and effectively promotes endoplasmic reticulum stress(ERS).In conclusion, UA can inhibit ovarian cancer cell proliferation, migration, colony formation, and may inhibit tumor cell autophagy by promoting tumor cell ERS, and ultimately promote ovarian cancer cell apoptosis.

Breast cancer, characterized by unique epidemiological patterns and significant heterogeneity, remains one of the leading causes of malignancy-related deaths in women. The increasingly nuanced molecular subtypes of breast cancer have enhanced the comprehension and precision treatment of this disease. The mechanisms of tumorigenesis and progression of breast cancer have been central to scientific research, with investigations spanning various perspectives such as tumor stemness, intra-tumoral microbiota, and circadian rhythms. Technological advancements, particularly those integrated with artificial intelligence, have significantly improved the accuracy of breast cancer detection and diagnosis. The emergence of novel therapeutic concepts and drugs represents a paradigm shift towards personalized medicine. Evidence suggests that optimal diagnosis and treatment models tailored to individual patient risk and expected subtypes are crucial, supporting the era of precision oncology for breast cancer. Despite the rapid advancements in oncology and the increasing emphasis on the clinical precision treatment of breast cancer, a comprehensive update and summary of the panoramic knowledge related to this disease are needed. In this review, we provide a thorough overview of the global status of breast cancer, including its epidemiology, risk factors, pathophysiology, and molecular subtyping. Additionally, we elaborate on the latest research into mechanisms contributing to breast cancer progression, emerging treatment strategies, and long-term patient management. This review offers valuable insights into the latest advancements in Breast Cancer Research, thereby facilitating future progress in both basic research and clinical application.

The work establishes a requirement for glucose-dependent coordination between energy production and redox homeostasis, which is fundamental for the survival of cancer cells that accumulate Cu and contributes to tumor growth.

Cancer-associated fibroblasts (CAFs) are abundant components of the tumor microenvironment (TME) of most solid malignancies and have emerged as key regulators of cancer progression and therapy response. Although recent technological advances have uncovered substantial CAF molecular heterogeneity at the single-cell level, defining functional roles for most described CAF populations remains challenging. With the aim of bridging CAF molecular and functional heterogeneity, this review focuses on recently identified functional interactions of CAF subtypes with malignant cells, immune cells, and other stromal cells in primary tumors and metastases. Dissecting the heterogeneous functional crosstalk of specific CAF populations with other components is starting to uncover candidate combinatorial strategies for therapeutically targeting the TME and cancer progression.

Cellular metabolism plays a pivotal role in the development and progression of pancreatic ductal adenocarcinoma (PDAC), with dysregulated metabolic pathways contributing to tumorigenesis and therapeutic resistance. Distinct metabolic heterogeneity in pancreatic cancer significantly impacts patient prognosis, as variations in metabolic profiles influence tumor behavior and treatment responses.

This review explores the intricate interplay between mitochondrial dynamics, mitophagy, and cellular metabolism in PDAC. We discuss the significance of mitophagy dysregulation in PDAC pathogenesis, emphasizing its influence on treatment responses and prognosis. Furthermore, we analyze the impact of mitochondrial dynamics alterations, including fission and fusion processes, on PDAC progression and tumorigenesis.

Targeting mitochondrial metabolism holds promise for advancing PDAC therapeutics. Ongoing clinical trials underscore the therapeutic potential of modulating key regulators of mitochondrial dynamics and mitophagy. Despite inherent challenges, these approaches offer diverse strategies to enhance treatment efficacy and improve patient outcomes.