Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive and metabolically rewired tumor microenvironment (TME). Although α-enolase (ENO1) is frequently overexpressed in PDAC and associated with poor prognosis, its functional role in TME remodeling remains unclear. This study investigated the role of ENO1 in plasmin-dependent transforming growth factor β (TGFβ) activation and metabolic adaptation in PDAC and evaluated the therapeutic potential of HuL001, a first-in-class humanized anti-ENO1 monoclonal antibody. Methods: ENO1 expression and clinical relevance were evaluated in PDAC tissues by immunohistochemistry. Mechanistic studies were performed using PDAC-monocyte co-culture systems, reverse transcription-quantitative PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), flow cytometry, and cell viability assays. The therapeutic effects of HuL001 were further assessed in multiple PDAC xenograft models. Results: Surface ENO1 expression was elevated in advanced PDAC and was associated with poorer overall survival. HuL001 suppressed monocyte-driven PDAC proliferation and reduced factors associated with M2-like macrophages (alternatively activated macrophages), including TGFB1, IL10, and VEGFA. Mechanistically, HuL001 inhibited ENO1-dependent plasmin-mediated activation of latent TGFβ and attenuated TGFβ-induced ENO1 expression, plasmin activity, hexokinase 2 (HK2) expression, and lactate production. In vivo, HuL001 inhibited PDAC growth and enhanced the antitumor efficacy of gemcitabine in three xenograft models, with greater suppression of tumor growth, intratumoral lactate, and active TGFβ than gemcitabine alone. Conclusion: These findings identify ENO1 as a functional driver of plasmin-dependent TGFβ activation and metabolic adaptation in PDAC and support HuL001 as a promising therapeutic strategy, particularly in combination with gemcitabine.

Despite the success of CDK4/6 inhibitors (CDK4/6i) in treating HR+/HER2- breast cancer (BC), some patients experience treatment failure due to CDK4/6i resistance. This study aimed to investigate whether targeting Aurora A kinase enhances CDK4/6 inhibitor sensitivity.

An Abemaciclib-resistant cell line (MCF7AR) was developed by treating MCF7 cells with gradually increasing concentrations of Abemaciclib. We evaluated the relative protein levels of p-RB, p-Aurora A, Aurora A, and USP22 in cell cultures, animal tissues, and clinical samples. The effect of Aurora A inhibition on reversing CDK4/6i resistance was assessed using cell viability assays and tumor xenograft experiments. We examined the relationship between Aurora A kinase activation levels and resistance to CDK4/6i.

CDK4/6i-resistant cell lines and patient samples exhibited elevated levels of phosphorylated Aurora A and retinoblastoma protein (RB). Previous studies have reported that RB inactivation can activate the spindle assembly checkpoint (SAC), leading to mitotic delay. High Aurora A activity counteracts the SAC-induced delay, thereby promoting mitosis. CDK4/6i treatment increased Aurora A protein levels through regulation by USP22, enhancing Aurora A activity and overcoming SAC-mediated cell cycle arrest. Combined therapy with Aurora A inhibitor (Aurora Ai) and CDK4/6i demonstrated synergistic antitumor effects both in vitro and in vivo. Clinical data suggest that HR+/HER2- patients with high levels of phosphorylated RB and Aurora A may exhibit resistance to CDK4/6i.

Aurora A contributes to CDK4/6i resistance by overcoming SAC delay and promoting mitosis. In RB-inactivated CDK4/6i-resistant cells, Aurora A inhibition may induce a synthetic lethal effect.

Objectives: Nasopharyngeal carcinoma (NPC) is an aggressive head and neck malignancy in which post-treatment recurrence and distant metastasis remain major contributors to poor clinical outcomes. Although microRNAs are important post-transcriptional regulators of tumor progression, the role of miR-320d in NPC remains incompletely understood. This study evaluated the biological role of miR-320d and explored whether it is involved in regulating neutrophil extracellular trap (NET) formation through the nuclear factor kappa-B (NF-κB)/interleukin-8 (IL-8) signaling axis. Methods: miR-320d was overexpressed in NPC cell lines S18 and 5-8F, and cell viability, migration, and invasion were evaluated. Integrated transcriptomic and proteomic analyses were performed to identify miR-320d-regulated genes, proteins, and pathways. Western blotting, immunohistochemistry, and immunofluorescence analyses were used to validate NET-associated proteins, including glycoprotein Ib platelet subunit alpha (GP1BA), histone deacetylase 10 (HDAC10), and fibrinogen gamma chain (FGG), as well as the expression of NET formation markers, including peptidyl arginine deiminase 4 (PADI4), myeloperoxidase (MPO), and neutrophil elastase (NE); and key components of the NF-κB/IL-8 axis. Results: miR-320d overexpression significantly inhibited the viability, migration, and invasion of both S18 and 5-8F cells. Multi-omics analyses indicated that miR-320d-regulated molecules were mainly enriched in NET-related pathways. Consistently, miR-320d reduced the expression of GP1BA, HDAC10, FGG, PADI4, MPO, and NE. Mechanistically, miR-320d suppressed NF-κB signaling, as shown by decreased phosphorylated NF-κB (p-NF-κB) and total NF-κB levels, and reduced IL-8 secretion in NPC cells. Conclusion: miR-320d may suppress NPC progression, at least in part, by attenuating NF-κB/IL-8-associated NET formation. These findings suggest that the miR-320d/NF-κB/IL-8/NET regulatory axis may participate in NPC progression and may warrant further translational investigation.

Lung adenocarcinoma (LUAD) has a poor prognosis, and effective metabolic biomarkers are still few. Glutamine metabolism is one of the central features of tumor metabolic reprogramming, but the cellular heterogeneity and clinical significance of glutamine metabolism in the LUAD tumor microenvironment (TME) remain unknown. The goal of this paper was to define glutamine metabolism on a single-cell basis and determine major regulators that have predictive value.

A single-cell RNA sequencing dataset (GSE149655) was combined with The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) and Gene Expression Omnibus (GEO) datasets in order to evaluate the metabolic activity and intercellular communication. The prognostic model was constructed on weighted gene co-expression network analysis (WGCNA), machine learning-based approaches, and least absolute shrinkage and selection operator (LASSO)-Cox regression to examine the characteristics of the immune system and sensitivity to drugs. Carried out CRISPR/Cas9 knockout experiments to prove the function of ANLN.

Glutamine metabolism activity and increased cell-cell communication were observed in mast cells. A gene signature of 4 genes (ANLN, CIP2A, MEST, WDR76) divided the patients into high-risk and low-risk groups; the survival of these two groups, immunosuppressant features of TME, and susceptibility to dasatinib were different. ANLN was also determined to be an essential prognostic driver, and downregulating it inhibited glutamine metabolism and the invasion properties of LUAD cells.

Mast cells are metabolic centers of LUAD, whereas ANLN is a mediator of the association between glutamine metabolism and the development of tumors, which offers possible treatment options to achieve precise prognostication and treatment goals.

Despite the use of targeted and/or immune-based therapeutic approaches, mortality rates among melanoma patients are high, mainly due to drug-induced resistance mechanisms. In parallel, alterations of epigenetic mechanisms (e.g., deregulated patterns of DNA methylation, aberrant histone modifications and abnormal expression levels of non-coding RNAs [ncRNAs]) have been associated not only with the pathophysiology of melanoma but also with the resistance against various immunotherapeutic drugs. In this review article, we discuss the involvement of different types of epigenetic mechanisms in melanoma progression. In addition, we report on melanoma's immune environment and immunosuppressive mechanisms while we highlight the role of immune checkpoint inhibitors (ICIs) as an anti-melanoma therapeutic approach. Moreover, we describe the underlying mechanism(s) by which deregulated epigenetic patterns promote drug resistance against ICIs and how epigenetic drugs (utilized either alone or in combination with various ICIs) can reverse immune resistance. Furthermore, we discuss the major limitations and future directions towards clinical translation of epigenetic drugs, mainly in combination with ICIs. Finally, we state the potential use of emerging technologies (e.g., single-cell transcriptomics and spatial transcriptomics), along with epigenetic priming for improvement of clinical implementation and therapeutic outcomes in melanoma management.

Background: Tumor-driven vascular remodeling is crucial for breast cancer metastasis; yet, the role of tumor-derived exosomal miRNAs in this process remains underexplored. This study aimed to investigate the clinical relevance and the underlying mechanism of breast cancer-derived exosomal miR-92b-3p in endothelial reprogramming. Methods: miR-92b-3p expression was evaluated in the TCGA cohort and clinical patient samples. The effects of exosomal miR-92b-3p from breast cancer cells on recipient human microvascular endothelial cells (HMVECs) were assessed using in vitro angiogenesis, migration, and permeability assays, alongside in vivo murine xenograft models. Mechanistic targets were validated via dual-luciferase and rescue experiments. Results: miR-92b-3p was significantly upregulated in breast cancer tissues and plasma exosomes, correlating with advanced stages, poor survival, and exhibiting high diagnostic accuracy. Breast cancer-derived exosomes effectively transferred miR-92b-3p into HMVECs, significantly promoting angiogenesis, endothelial migration, and transendothelial permeability. In vivo, overexpression of miR-92b-3p accelerated tumor growth, vascularization, and circulating tumor cell (CTC) dissemination. Mechanistically, exosomal miR-92b-3p directly targeted and suppressed PTEN in endothelial cells; moreover, restoring PTEN expression fully abrogated the exosome-induced pro-angiogenic and hyperpermeable phenotypes. Conclusions: Breast cancer-derived exosomal miR-92b-3p disrupts the vascular barrier and promotes tumor angiogenesis by targeting endothelial PTEN, thereby facilitating metastasis. Circulating exosomal miR-92b-3p represents a promising candidate liquid-biopsy biomarker for breast cancer progression.

Gastric cancer (GC) is one of the malignant tumors with high incidence and mortality worldwide. It has concealed early symptoms, poor prognosis for advanced patients, and limited efficacy of conventional treatments. Metabolic reprogramming is a core hallmark of cancer, among which amino acid metabolic reprogramming plays a critical regulatory role in the initiation and progression of GC. By linking intracellular energy supply, biosynthetic demands, and tumor microenvironment remodeling, it participates in immune escape, redox homeostasis maintenance, and therapeutic resistance. Dysregulation of key amino acids, including arginine, tryptophan, glutamine, branched-chain amino acids, serine/glycine, and aspartic acid, as well as altered expression and activity of rate-limiting enzymes and key catalytic enzymes, collectively drive the proliferation, invasion, metastasis, and stemness maintenance of GC cells. These metabolic enzymes can serve as potential biomarkers for the diagnosis and prognosis of GC, and are also important targets for precision therapy. At present, progress has been made in the development of inhibitors targeting key enzymes in amino acid metabolism. Single-target therapy or its combination with chemotherapy and immunotherapy has shown promising application prospects, but challenges such as clinical translation bottlenecks and unclear drug resistance mechanisms still exist. This review systematically summarizes the roles and molecular mechanisms of key amino acid metabolic enzymes in the occurrence and development of GC, and sorts out the research status of related targeted therapies, so as to provide references for basic research and clinical translation of metabolic precision therapy for GC.

Background: The melanoma-associated antigen-A1 (MAGE-A1) demonstrates tumor-restricted expression patterns in diverse malignancies, positioning it as an attractive therapeutic target. This investigation aimed to engineer and validate a novel antibody-drug conjugate with oxaliplatin targeting MAGE-Al (MIg-OXA), a novel antibody-drug conjugate targeting MAGE-A1, while assessing its therapeutic potential against MAGE-A1-expressing lung adenocarcinoma through both cellular and animal models. Methods: We generated a MAGE-A1-specific immunoglobulin G (IgG) antibody (MIgG) and subsequently conjugated it with oxaliplatin (OXA) to produce MIgG-OXA. The conjugate's binding specificity and cellular uptake were verified through cell-based enzyme-linked immunosorbent assay (ELISA), flow cytometric analysis, and immunofluorescence microscopy. Functional assessments included Cell Counting Kit-8 (CCK-8) viability assays, transwell migration studies, apoptosis detection, and antibody-dependent cell-mediated cytotoxicity (ADCC) evaluation to determine anti-neoplastic activity in cultured cells. Therapeutic efficacy in living organisms was examined using lung adenocarcinoma (LUAD) xenograft-bearing athymic mice. Results: Our data confirmed successful synthesis and validation of MIgG-OXA, which demonstrated selective recognition of MAGE-A1-expressing LUAD cell populations and facilitated controlled OXA release. When compared to unconjugated OXA, MIgG-OXA displayed enhanced tumor suppression in both cultured LUAD cells and transplanted tumor models. Conclusion: These findings collectively indicate that MIgG-OXA holds substantial promise as a precision therapeutic approach for patients harboring MAGE-A1-positive LUAD.

Objectives: Oral squamous cell carcinoma (OSCC) is a common and deadly cancer affecting the oral cavity. This study aims to explore the regulatory role and molecular mechanism of miR-548ae-3p in OSCC proliferation, invasion, and lipid metabolism, as well as the therapeutic potential of isoliquiritigenin (ISL) targeting OSCC lipid metabolism. Methods: Expression levels of miR-548ae-3p were measured in OSCC cell lines and normal oral keratinocytes using real-time quantitative polymerase chain reaction. Functional assays, such as cell counting Kit-8 proliferation and Transwell invasion assays, evaluated the effects of miR-548ae-3p overexpression in CAL-27 and SCC-25 cells. Bioinformatic prediction and dual-luciferase reporter assays investigated interactions among miR-548ae-3p, hsa_circRNA_0001794 (circPOLB), and cellular myelocytomatosis oncogene (c-MYC). Lipid metabolism was assessed using lipid droplet staining, fatty acid oxidation assays, total fatty acids and palmitic acid quantification, and fatty acid-binding protein 5 (FABP5) expression analysis. The inhibitory effects of ISL on OSCC lipid metabolism and invasiveness were also examined. Results: MiR-548ae-3p was downregulated in OSCC cells compared to normal keratinocytes (n = 3, p < 0.001). miR-548ae-3p overexpression inhibited the proliferation and invasion of CAL-27 and SCC-25 cells (n = 3, p < 0.001). CircPOLB functions as a molecular sponge for miR-548ae-3p, which in turn targets c-MYC, a key oncogene. MiR-548ae-3p overexpression reduced lipid droplet accumulation, fatty acid oxidation, total fatty acid content, and intracellular palmitic acid levels, accompanied by downregulation of FABP5 (n = 3, p < 0.001). Furthermore, ISL treatment decreased FABP5 expression, fatty acid metabolism, and invasive capacity of OSCC cells (n = 3, p < 0.001), supporting its potential as a therapeutic agent. Conclusions: MiR-548ae-3p displays tumor-suppressive activity in OSCC, restraining proliferation, invasion, and fatty-acid metabolism through engagement of the circPOLB/c-MYC axis and is associated with reduced FABP5 expression. Targeting lipid metabolism using agents like ISL could be a promising approach for treating OSCC.

Objectives: Transcriptomic profiling has enabled the classification of Diffuse Large B-Cell Lymphoma (DLBCL) into distinct subtypes, such as Germinal Center B-cell-like (GCB) and Activated B-cell-like (ABC), primarily in HIV-negative patients. However, HIV-associated DLBCL may follow different molecular mechanisms due to immune dysregulation. This study aimed to characterize the transcriptomic landscape of HIV-related DLBCL to identify distinct subtypes and deregulated pathways with potential theranostic implications. Methods: Twelve formalin-fixed, paraffin-embedded DLBCL samples from HIV-positive patients were analyzed using Agilent's microarray. Quantile normalization and unsupervised hierarchical clustering were performed to classify tumors based on gene expression profiles. Results: Two distinct transcriptomic subgroups were identified. TP53 and BCL7A were overexpressed in cluster I, while BCL2 was overexpressed in cluster II. Notably, the "immune system development" pathway was under expressed in cluster I compared to cluster II. Conclusions: Our findings reveal two molecularly distinct subtypes of HIV-associated DLBCL, likely driven by differences in tumor microenvironment and immune status. These transcriptomic profiles may guide future targeted therapies. Further validation in larger cohorts and integration with proteomic and clinical data are warranted to develop a comprehensive theranostic framework.