Search Results (784)

Background: Patients with systemic sclerosis have a significantly increased incidence of developing various solid malignancies within a few years of systemic sclerosis onset, but the mechanism of tumor promotion is not well understood. The tight skin (TSK) mouse has been a valuable model for investigating systemic sclerosis-related pathologies due to increased extracellular matrix deposition, fibrosis in connective tissues, and altered immune cell activation. Despite the role of extracellular matrix and fibrosis in cancer progression, the potential of the TSK mouse as a model for cancer studies is unexplored. Methods: To investigate the impact of the altered microenvironment in TSK mice on cancer progression, we compared the tumor-forming capabilities (by subcutaneous and intraperitoneal injection) in TSK mice and WT mice using syngeneic breast cancer, melanoma, and ovarian cancer cell lines. We used bulk and single-cell RNA sequencing to characterize these tumors and identify the changes in the TSK microenvironment that promote cancer formation. Results: In all three cancer types, TSK mice exhibited more invasive subcutaneous tumors in comparison to WT controls, underscoring the role of the TSK subcutaneous microenvironment in promoting cancer progression. Furthermore, the heightened invasiveness of ovarian tumors implanted intraperitoneally suggests that the peritoneal microenvironment in TSK mice also promotes tumor progression. Single-cell RNA sequencing analyses of subcutaneous tumors from TSK and WT mice revealed tumor-specific changes in the composition and phenotype of various cell populations. The most consistent alteration in TSK mice included a higher neutrophil-to-lymphocyte ratio and an enrichment in profibrotic subpopulations of myofibroblasts and macrophages. Conclusions: Our research unveils the TSK mouse as a valuable model for studying the intricate connections between systemic sclerosis and cancer Full article

The field of oncology has been extensively studied to design more effective and efficient treatments. This review explores the advanced techniques that are transforming our comprehension of cancer and its constituents. Specifically, it highlights the signaling pathways that drive tumor progression, angiogenesis, and resistance to therapy, as well as the modern approaches used to identify and characterize these pathways within the tumor microenvironment (TME). Key pathways discussed in this review include vascular endothelial growth factor (VEGF), programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and various extracellular matrix (ECM) pathways. Conventional methods of diagnosis have yielded sufficient knowledge but have failed to reveal the heterogeneity that exists within the TME, resulting in gaps in our understanding of the cellular interaction and spatial dynamics. Single-cell sequencing (SCS) and spatial transcriptomics (ST) are effective tools that can enable the dissection of the TME with the resolution capacity of a single cell. SCS allows the capture of the unique genetic and transcriptomic profiles of individual cells along with rare cell types and new therapeutic targets. ST complements this by providing a spatial map of gene expression, showing the gene expression profiles within the tumor tissue at specific sites with good accuracy. By mapping gene expression patterns at a single cell level and correlating them with the spatial locations, researchers can uncover the intricate networks and microenvironmental influences that contribute to tumor heterogeneity. Full article

Ectopic expression of human leukocyte antigen class II (HLA-II) on tumor cells correlates with anti-tumor immunity and prognosis in various cancers, but its role in esophageal squamous cell carcinoma (ESCC) remains unclear. Methods: HLA-II expression was evaluated in 34 ESCC tissue sections and a 102-sample tissue microarray (TMA) using immunohistochemistry (IHC) and in 10 ESCC cell lines via flow cytometry. Transcriptome sequencing of KYSE270, KYSE180, KYSE450, and KYSE510 was performed to investigate HLA-II regulatory mechanisms, while tumor samples from 104 ESCC patients were analyzed for neoantigen load. The prognostic significance of neoantigen burden was assessed using Cox regression. Results: HLA-II was ectopically expressed in ESCC, with positivity rates of 20.59% (34 tissues) and 25.49% (TMA). Among 10 ESCC cell lines, only KYSE270 exhibited spontaneous HLA-II expression. Transcriptome analysis revealed 1278 KYSE270-specific genes enriched in immune-related pathways (e.g., “Cytokine–cytokine receptor interaction”), suggesting immune-mediated HLA-II regulation. IFN-γ stimulation induced HLA-II expression in KYSE180, KYSE450, and KYSE510, indicating broader inducible HLA-II potential. In 104 patients, MHC-II-restricted neoantigen burden varied widely (0–75) and lacked direct correlation with HLA-II expression. Additionally, MHC-II-restricted neoantigen load was not significantly associated with overall survival (p > 0.05). Conclusion: Ectopic HLA-II expression in ESCC may influence the tumor immune microenvironment, while the prognostic value of MHC-II-restricted neoantigen burden in ESCC remains unclear, providing potential implications for immunotherapy strategies. Full article

Background: Macrophages are key components of the tumor microenvironment and play a critical role in melanoma progression. However, the dynamics of different macrophage subsets, particularly CD68⁺ and CD163⁺ populations, in relation to tumor thickness and stage remain insufficiently characterized. Objective: This study aimed to quantitatively assess intratumoral and peritumoral CD68⁺ and CD163⁺ macrophages in cutaneous melanoma and to investigate their associations with Breslow thickness, pT stage, and AJCC stage. Methods: We conducted a retrospective cohort study of 126 patients with cutaneous melanoma (AJCC stages IA–IIID). Tumor samples were examined histologically and immunohistochemically for CD68⁺ and CD163⁺ macrophages, and quantitative analysis was performed in intratumoral and peritumoral regions. Results: This study included 126 patients with cutaneous melanoma, ranging in stage from IA to IIID. Histopathological analysis revealed that melanoma tissues were primarily composed of irregular clusters of atypical melanocytic cells infiltrating the dermis and subcutaneous fat. Immunohistochemical staining identified CD68⁺ and CD163⁺ macrophages both within the tumor and in the surrounding stroma. Macrophage infiltration significantly increased with tumor thickness (Breslow) and progression to more advanced stages. Specifically, at Breslow thickness <1.0 mm, the mean number of CD68⁺ macrophages in the intratumoral zone was 29.7 ± 4.3 cells, increasing to 70.3 ± 6.4 cells in tumors >4.0 mm. CD163⁺ macrophages showed similar trends, with a rise from 15.6 ± 2.8 cells at <1.0 mm to 39.8 ± 4.6 cells at >4.0 mm in the intratumoral zone. Additionally, macrophage density was higher in tumors with ulceration, and both CD68⁺ and CD163⁺ macrophage numbers increased progressively with tumor stage, particularly in advanced stages. The number of CD68⁺ macrophages at stage IA in the intratumoral zone was 21.6 ± 3.1 cells and increased to 56.4 ± 6.8 cells at stage IIID, while CD163⁺ macrophages rose from 13.8 ± 3.2 cells at stage IA to 36.4 ± 4.6 cells at stage IIID. This suggests that macrophage infiltration, particularly CD163⁺ cells, correlates with melanoma progression. Conclusions: Our findings highlight distinct spatial and phenotypic patterns of macrophage infiltration in melanoma progression. The prominent increase in CD68⁺ and CD163⁺macrophages suggests their important role in tumor-associated immunomodulation. Further studies are warranted to elucidate macrophage polarization states and their prognostic and therapeutic implications in melanoma. Full article

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of certain hematologic malignancies, yet its success in solid tumors has been limited by antigen heterogeneity, an immunosuppressive tumor microenvironment, and barriers to cell trafficking and persistence. To expand the reach of cellular immunotherapy, multiple immune cell types—γδ T cells, invariant NKT cells, virus-specific T cells, natural killer (ΝΚ) cells, and myeloid effectors such as macrophages and dendritic cells—are now being explored as alternative or complementary CAR platforms. Each lineage brings unique advantages, such as the innate cytotoxicity and safety profile of CAR NK cells, the tissue infiltration and microenvironment-modulating capacity of CAR macrophages, or the MHC-independent recognition offered by γδ T cells. Recent advances in pharmacological strategies, synthetic biology, and artificial intelligence provide additional opportunities to overcome barriers and optimize CAR design and manufacturing scale-up. Here, we review the state of the art in engineering diverse immune cells for solid tumor therapy, highlight safety considerations across autologous, allogeneic, and in vivo CAR cell therapy approaches, and provide our perspective on which platforms might best address current unmet clinical needs. Collectively, these developments lay the foundation for next-generation strategies to achieve durable immunotherapy responses in solid tumors. Full article

Background: The SUMO E3 ligase PIAS1 (Protein Inhibitor of Activated STAT1) regulates pathways such as TGFβ signaling and has been implicated in multiple cancers. However, its role in the tumor microenvironment (TME), particularly in non-malignant stromal and immune cells, remains poorly understood. This study aimed to characterize the expression and functional relevance of PIAS1 within the TME of oral squamous cell carcinoma (OSCC). Methods: PIAS1 protein expression was assessed via immunohistochemistry (IHC) on OSCC tissue microarrays. Single-cell RNA-sequencing (scRNA-seq) datasets from OSCC tumors and normal tissues were analyzed to map cell-type-specific PIAS1 expression. Downstream effects were evaluated using differential gene expression, Ingenuity Pathway Analysis (IPA), gene set enrichment analysis (GSEA), and cell–cell communication inference. Results: IHC analysis revealed that higher stromal PIAS1 levels correlated with improved survival. scRNA-seq analysis showed an increase in the proportion of PIAS1-expressing cells across most stromal and immune cell populations within OSCC-derived tumors compared to their counterparts in adjacent normal tissue. However, when comparing PIAS1-positive cells, expression levels were significantly reduced in cancer cells, CAFs, TAMs, T cells, and endothelial cells within the TME. PIAS1-positive CAFs, TAMs, and T cells exhibited activation of apoptotic and tumor-suppressive pathways, while PIAS1-negative counterparts showed enrichment of immunosuppressive signaling and immune checkpoint expression. Cell–cell communication analyses indicated that PIAS1 fosters an immune-activated TME by promoting pro-inflammatory signaling, M1-like TAM polarization, and T cell activation. Conclusions: PIAS1 expression in stromal and immune cells is associated with tumor-suppressive reprogramming of the OSCC microenvironment. These findings position PIAS1 as a potential modulator of anti-tumor immunity and candidate target for therapeutic intervention. Full article

Multilayer platforms have emerged as promising tools in the field of wound healing, offering a multifaceted approach to promote effective and accelerated tissue regeneration. This review article aims to provide a comprehensive overview of the various multilayer platforms employed in wound healing applications, highlighting their structure, fabrication methods, and potential mechanisms of action. The first section of the review focuses on the design and composition of multilayer platforms, encompassing different materials such as polymers, hydrogels, and biocompatible scaffolds. It discusses the significance of each layer in terms of its specific functionalities, including cell adhesion, drug/bioactive factor loading, antimicrobial properties, and mechanical support. The second section of the review delves into the mechanisms of action associated with multilayer platforms in wound healing. It discusses how these platforms facilitate wound closure, promote angiogenesis, modulate inflammation, and enhance tissue regeneration. The article also examines the role of multilayer platforms in providing a physical barrier against external pathogens, reducing the risk of infection, and creating a favorable microenvironment for wound healing. Overall, this review highlights the significant advancements made in the field of multilayer platforms for wound healing and underscores their potential as versatile therapeutic strategies. Full article

Proteasome subunit beta type-9 (PSMB9), a member of the proteasome beta subunit family, encodes the pivotal β1i component of the immunoproteasome. PSMB9 plays a crucial role in antigen processing and presentation; however, its comprehensive role in orchestrating a tumor-immune landscape and regulating the anti-tumor immune responses remains unexplored. Here we investigated the context-dependent functions of PSMB9 by integrating multi-omics data from The Cancer Genome Atlas, Genotype-Tissue Expression database, Human Protein Atlas, Tumor Immunotherapy Gene Expression Resource, and multiple other databases. Moreover, we explored the predictive value of PSMB9 in multiple immunotherapy cohorts and investigated its functional relevance in CAR-T therapy using genome-scale CRISPR/Cas9 screening, gene knockout cell line in vitro, and clinical cohort validation. We found widespread dysregulation in PSMB9 across cancers, predominantly upregulated in most malignancies and associated with advanced pathological stages in specific contexts. PSMB9 was also broadly and negatively correlated with tumor stemness indices. Crucially, PSMB9 expression was robustly linked to anti-tumor immunity by being significantly correlated with immune-pathway activation (e.g., IFN response, cytokine signaling), immune regulatory and immune checkpoint gene expression, and enhanced infiltration of T cells across nearly all tumor types. Consequently, elevated PSMB9 predicted superior response to immune checkpoint inhibitors in multiple cohorts, showing comparable predictive power to established predictive signatures. Furthermore, CRISPR/Cas9 screening identified PSMB9 loss as a novel mechanism of resistance to CD19 CAR T cell therapy, with PSMB9-deficient tumor cells exhibiting a survival advantage under CAR-T pressure, supported by trends in clinical CAR-T outcomes. Our study uncovers PSMB9 as a previously unrecognized critical regulator of the tumor immune landscape in a pan-cancer scope, whose expression orchestrates key immune processes within the tumor microenvironment and serves as a potent biomarker for patient prognosis. Critically, we first established PSMB9 as a novel prognostic indicator for both checkpoint blockade and CAR-T cell therapies, highlighting its dual role as a crucial immune modulator and a promising biomarker for guiding T cell-based immunotherapy strategies across diverse human cancers. Full article

Background/Objectives: Cancer-associated fibroblasts (CAFs) play a pivotal role in the tumor microenvironment. We conducted an analysis using RNA sequencing to identify specific markers for CAFs compared to normal fibroblasts (NFs) in non-small-cell carcinoma (NSCLC). Methods: CAFs and NFs were isolated and cultured from tumor tissues (primary tumor or metastatic lymph nodes) and matched non-tumor tissues, respectively. Bulk RNA sequencing was conducted on isolated CAFs and normal fibroblast NFs. Differential expressions, gene set enrichment, and CAF subpopulation prediction analyses were performed. Results: During the study period, 27 CAFs and 12 NFs were isolated and cultured from tumor and non-tumor tissues in patients with treatment-naïve NSCLC. Among them, 22 CAFs and 11 NFs were included in the RNA sequencing analysis. The 22 CAF samples consisted of 12 adenocarcinomas and 10 squamous cell carcinomas (SqCC), with 16 samples from the lungs and 6 samples from the lymph nodes. Notably, COL11A1, GREM1, CD36, and GAS6 showed a higher expression in CAFs than in NFs, whereas TNC and CXCL2 were more abundantly expressed in NFs. CD36 levels were elevated in CAFs from lymph nodes (LN-CAFs) compared with those from lung specimens (Lung-CAFs) and NFs. COL11A1 levels in Lung-CAFs surpassed those in LN-CAFs and NFs. Both GREM1 and GAS6 showed a strong expression in Lung-CAFs and LN-CAFs relative to NFs. CAFs exhibited features of the myofibroblast CAF subpopulation, whereas NFs displayed traits of the antigen-presenting CAF subtype. In the co-culture model of CAFs and THP-1 cells, the knockdown of GREM1 or GAS6 in CAFs significantly decreased the M2 marker expression in macrophages. Conclusions: In NSCLC, GREM1 and GAS6 can be valuable diagnostic targets for CAFs from primary tumors and metastatic sites; they warrant further study. Full article

Thallium (Tl) is a non-essential and highly toxic heavy metal capable of replacing potassium (K⁺) in biological systems, leading to mitochondrial dysfunction, oxidative stress, and inhibition of protein synthesis. In humans, the estimated oral lethal dose ranges from 10 to 15 mg/kg, with acute mortality rates of 6–15% and chronic neurological sequelae in up to 55% of survivors. Environmental releases of thallium of up to 5000 metric tons annually from industrial and mining activities, combined with its high oral bioavailability and nonspecific multisystemic symptoms, underscore the urgent need for more effective therapeutic strategies. This review summarizes current evidence on Tl toxicity, including its mechanisms of action, clinical manifestations, and available treatments. It emphasizes the strategic selection of biological models: simple organisms such as Caenorhabditis elegans and Drosophila melanogaster enable high-throughput screening and early biomarker detection; zebrafish (Danio rerio) provide vertebrate-level evaluation of multi-organ effects; and rodent models offer systemic toxicokinetic and therapeutic validation. Human-derived organoids and induced pluripotent stem cell (iPSC) systems recreate tissue-specific microenvironments, allowing translational assessment of mitochondrial, neuronal, and cardiac toxicity. Integrating these models within a tiered and complementary framework, alongside environmental and clinical surveillance, can accelerate the development of targeted treatments and strengthen public health responses to Tl exposure. Full article

Background/Objectives: Obesity and type 2 diabetes mellitus (T2DM) profoundly disrupt lipid metabolism within local microenvironments of skeletal muscle and its associated connective tissues, including adipose tissue, bone, and fascia. However, the role of local communication between skeletal muscle and its proximal connective tissues in propagating metabolic dysfunction is incompletely understood. This narrative review synthesizes current evidence on these local metabolic interactions, highlighting novel insights and existing gaps. Methods: We conducted a comprehensive literature analysis of primary research published in the last decade, sourced from PubMed, Web of Science, and ScienceDirect. Studies were selected for relevance to skeletal muscle, adipose tissue, fascia, and bone lipid metabolism in the context of obesity and T2DM, with emphasis on molecular, cellular, and paracrine mechanisms of local crosstalk. Findings were organized into thematic sections addressing physiological regulation, pathological remodeling, and inter-organ signaling pathways. Results: Our synthesis reveals that local lipid dysregulation in obesity and T2DM involves altered fatty acid transporter dynamics, mitochondrial overload, fibro-adipogenic remodeling, and compartment-specific adipose tissue dysfunction. Crosstalk via myokines, adipokines, osteokines, bioactive lipids, and exosomal miRNAs integrates metabolic responses across these tissues, amplifying insulin resistance and lipotoxic stress. Emerging evidence highlights the underappreciated roles of fascia and marrow adipocytes in regional lipid handling. Conclusions: Collectively, these insights underscore the pivotal role of inter-tissue crosstalk among skeletal muscle, adipose tissue, bone, and fascia in orchestrating lipid-induced insulin resistance, and highlight the need for integrative strategies that target this multicompartmental network to mitigate metabolic dysfunction in obesity and T2DM. Full article

Schwann cells (SCs) are the primary glial cells of the Peripheral Nervous System (PNS), which insulate and provide protection and nutrients to the axons. Technological and experimental advances in neuroscience, focusing on the biology of SCs, their interactions with other cells, and their role in the pathogenesis of various diseases, have paved the way for exploring new treatment strategies that aim to harness the direct protective or causative properties of SCs in neurological disorders. SCs express cytokines, chemokines, neurotrophic growth factors, matrix metalloproteinases, extracellular matrix proteins, and extracellular vesicles, which promote the inherent potential of the injured neurons to survive and accelerate axonal elongation. The ability of SCs to support the development and functioning of neurons is lost in certain hereditary, autoimmune, metabolic, traumatic, and toxic conditions, suggesting their role in specific neurological diseases. Thus, targeting, modifying, and replacing SC strategies, as well as utilizing SC-derived factors and exosomes, have been considered novel therapeutic opportunities for neuropathological conditions. Preclinical and clinical data have demonstrated that SCs and SC-derived factors can serve as viable cell therapy for reconstructing the local tissue microenvironment and promoting nerve anatomical and functional recovery in both peripheral and central nerve injury repair, as well as in peripheral neuropathies. However, despite the promising successes of genetic engineering of SCs, which are now in preclinical and clinical trials, improving tactics to obtain ‘repair’ SCs and their products from different sources is the key goal for future clinical success. Finally, further development of innovative therapeutic approaches to target and modify SC survival and function in vivo is also urgently needed. Full article

Glioblastoma is an aggressive and prevalent form of brain cancer characterized by rapid tumor cell migration and invasion into surrounding healthy tissues, making it resistant to conventional treatments. Despite advances in therapeutic approaches, patient prognosis remains poor, with a median survival of approximately 15 months. Tumor cell infiltration along perivascular spaces and white matter tracts is a major driver of recurrence, underscoring the need for experimental models that accurately capture these invasive behaviors. Animal models remain indispensable for this purpose, offering insights that cannot be fully replicated in vitro. This review focuses on applying animal models to elucidate the mechanisms underlying glioblastoma cell migration and invasion, which remain critical to improving therapeutic outcomes. By comparing the advantages of animal models with in vitro systems, we highlight the unique insights animal models provide, particularly in capturing the intricate dynamics of tumor cell motility. In particular, patient-derived xenograft (PDX) models preserve patient-specific heterogeneity and invasion patterns, such as white matter tract and perivascular infiltration, enabling clinically relevant drug testing. Zebrafish xenografts provide real-time, high-resolution visualization of tumor-vascular interactions, facilitating rapid assessment of invasion dynamics and early-stage drug screening. Genetically engineered models (GEM) allow precise discrimination of how defined genetic alterations drive specific invasive routes in the brain. Furthermore, we explore the use of advanced imaging techniques in these models to monitor tumor progression in real time. Moreover, we discuss the major drawbacks of these animal models, such as incomplete immune components and tumor microenvironment recapitulation. Ultimately, animal models are essential for bridging the gap between basic research and clinical application, offering a powerful platform for developing targeted strategies to combat glioblastoma’s relentless progression. Full article

Diabetes is emerging as a significant health and societal concern globally, impacting both young and old populations. In individuals with diabetic foot ulcers (DFUs), the wound healing process is hindered due to abnormal glucose metabolism and chronic inflammation. Minor injuries, blisters, or pressure sores can develop into chronic ulcers, which, if left untreated, may lead to serious infections, tissue necrosis, and eventual amputation. Current management techniques include debridement, wound dressing, oxygen therapy, antibiotic therapy, topical application of antibiotics, and surgical skin grafting, which are used to manage diabetic wounds and foot ulcers. This review focuses on a hydrogel-based strategy for phase-wise targeting of DFUs, addressing sequential stages of diabetic wound healing: hemostasis, infection, inflammation, and proliferative/remodeling phases. Hydrogels have emerged as a promising wound care solution due to their unique properties in providing a suitable wound-healing microenvironment. We explore natural polymers, including hyaluronic acid, chitosan, cellulose derivatives, and synthetic polymers such as poly (ethylene glycol), poly (acrylic acid), poly (2-hydroxyethyl methacrylate, and poly (acrylamide), emphasizing their role in hydrogel fabrication to manage DFU through phase-dependent strategies. Recent innovations, including self-healing hydrogels, stimuli-responsive hydrogels, nanocomposite hydrogels, bioactive hydrogels, and 3D-printed hydrogels, demonstrate enhanced therapeutic potential, improving patient outcomes. This review further discusses the applicability of various hydrogels to each phase of wound healing in DFU treatment, highlighting their potential to advance diabetic wound care through targeted, phase-specific interventions. Full article

In the tumor microenvironment, various immune and stromal cells, such as fibroblasts and vascular endothelial cells, contribute to tumor growth and progression by interacting with cancer cells. Tumor-associated macrophages (TAMs) have attracted attention as major players in the tumor microenvironment. The origin of TAMs is believed to be the infiltration of monocytes derived from bone marrow progenitor cells into tumor tissues and their differentiation into macrophages, whereas tissue-resident macrophages derived from yolk sacs have recently been reported. TAMs infiltrating tumor tissues act in a tumor-promoting manner through immunosuppression, angiogenesis, and the promotion of cancer cell invasion. Reflecting the nature of TAMs, increased TAM invasion and TAM-specific gene expression in tumor tissues may be the new biomarkers for cancer. Moreover, new therapeutic strategies targeting TAMs, such as transformation into immunostimulatory macrophages, suppression of TAM infiltration, and promotion of phagocytosis, are being investigated, and many clinical trials are underway. As the origin and function of TAMs are further elucidated, TAM-targeted therapy is expected to become a new option for the immunotherapy of various cancers, including oral cancers. Full article