Search Results (5,565)

This narrative review consolidates existing evidence about the interaction between Epstein-Barr virus (EBV) and SARS-CoV-2 in cancer development. EBV is a recognized oncogenic driver, whereas COVID-19 may heighten cancer risk by immunological dysregulation, persistent inflammation, and reactivation of latent viruses. We underscore molecular similarities (e.g., NF-κB activation, T-cell exhaustion) and clinical ramifications for high-risk individuals, stressing the necessity for interdisciplinary research to alleviate dual viral risks. EBV, a well-known oncogenic virus, has been linked to numerous malignancies, including lymphomas, nasopharyngeal carcinoma, and gastric cancer. Through the production of viral proteins that interfere with immune evasion, cellular signaling, and genomic integrity, it encourages malignant transformation and ultimately results in unchecked cell proliferation. Because of its capacity to induce tissue damage, immunological dysregulation, and chronic inflammation, COVID-19, which is brought on by the SARS-CoV-2 virus, has become a possible carcinogen. The virus’s influence on cellular pathways and its long-term effects on the immune system may raise the chance of malignancy, particularly in people with pre-existing vulnerabilities, even if direct correlations to cancer are still being investigated. When two viruses co-infect a host, the review highlights the possibility of synergistic effects that could hasten the development of cancer. It describes how overlapping mechanisms like inflammation, immune suppression, and viral reactivation may be used by a combined EBV and COVID-19 infection to exacerbate carcinogenic processes. Gaining an understanding of these relationships is essential for creating tailored treatment plans and enhancing cancer prevention in high-risk groups. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by rapid proliferation and infiltration of immune cells into tumor microenvironment (TME). The treatment of TNBC still remains challenging due to the lack of expression of effective molecular targets pertaining to the tumor cell itself. In TNBC standard of care, therapies such as chemotherapy, together with recently introduced immunotherapy with checkpoint inhibitors, often do not result in durable clinical response. Therefore, better understanding of complex interactions between tumor cells, immune cells, and stromal cells mediated by multiple cytokines, chemokines, enzymes, and metabolites in TME is crucial for understanding the mechanisms that underlie tumor cell immune evasion strategies. The aim of this review is to give comprehensive overview of immune cell network and their interactions with cells in TME and possibilities for therapeutic targeting of TME in TNBC. We discuss cancer-associated fibroblasts (CAFs) as an important recently characterized player in TNBC with respect to their role in interactions with immune cells and their impact on tumor invasion. Based on the recently accumulated knowledge, therapies targeting immune suppressive mechanisms and CAF-related tumor-promoting mechanisms in TME hold great potential for clinical evaluation in TNBC. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with poor prognosis. T cell exhaustion (TEX) is a key factor in tumor immune evasion and therapeutic resistance. In this study, we integrated single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (RNA-seq) data to characterize TEX-related transcriptional features in HCC. Methods: We first computed TEX scores for each sample using a curated 65-gene signature and classified them into high-TEX and low-TEX groups by the median score. Differentially expressed genes were identified separately in scRNA-seq and bulk RNA-seq data, then intersected to retain shared candidates. A 26-gene prognostic signature was derived from these candidates via univariate Cox and LASSO regression analysis. Results: The high-TEX group exhibited increased expression of immune checkpoint molecules and antigen presentation molecules, suggesting a tumor microenvironment that is more immunosuppressive but potentially more responsive to immunotherapy. Functional enrichment analysis and protein–protein interaction (PPI) network construction further validated the roles of these genes in immune regulation and tumor progression. Conclusions: This study provides a comprehensive characterization of the TEX landscape in HCC and identifies a robust gene signature associated with prognosis and immune infiltration. These findings highlight the potential of targeting TEX-related genes for personalized immunotherapeutic strategies in HCC. Full article

Immunotherapy, particularly approaches that combine tumor-specific vaccines with immune checkpoint modulation, represents a promising strategy for overcoming tumor immune evasion. While most mRNA-based cancer vaccines focus solely on antigen delivery, there is a need for platforms that simultaneously enhance antigen presentation and modulate the tumor microenvironment to increase therapeutic efficacy. This study presents a novel dual-nanolipid exosome (NLE) platform that simultaneously delivers MUC1 mRNA and CTLA-4-targeted siRNA in a single system. These endogenous lipid-based nanoparticles are structurally designed to mimic exosomes and are modified with mannose to enable selective targeting to dendritic cells (DCs) via mannose receptors. The platform was evaluated both in vitro and in vivo in terms of mRNA encapsulation efficiency, nanoparticle stability, and uptake by DCs. The co-delivery platform significantly enhanced antitumor immune responses compared to monotherapies. Flow cytometry revealed a notable increase in tumor-infiltrating CD8⁺ T cells (p < 0.01), and ELISPOT assays showed elevated IFN-γ production upon MUC1-specific stimulation. In vivo CTL assays demonstrated enhanced MUC1-specific cytotoxicity. Combined therapy resulted in immune response enhancement compared to vaccine or CTLA-4 siRNA alone. The NLE platform exhibited favorable biodistribution and low systemic toxicity. By combining targeted delivery of dendritic cells, immune checkpoint gene silencing, and efficient antigen expression in a biomimetic nanoparticle system, this study represents a significant advance over current immunotherapy strategies. The NLE platform shows strong potential as a modular and safe approach for RNA-based cancer immunotherapy. Full article

Background: Irradiation (IR) targets cancer cells, but also the tumor microenvironment, including the tumor’s blood vessels. In addition to tumor endothelial cell (TEC) apoptosis, IR can lead to TEC activation, potentially increasing immune cell infiltration. However, the changes underlying the IR-induced activation of endothelial cells (ECs) are poorly understood. This study investigated dose- and time-dependent molecular and functional responses of murine and human EC lines to IR in vitro and TECs in vivo in murine tumor models of colorectal carcinoma. Methods: HUVEC, EA.hy926, and Hulec5a, as well as murine bEND.3, 2H11, and SVEC4-10 EC lines, were irradiated with single doses of 2–10 Gy. EC proliferation and survival after IR were assessed by staining all nuclei (Hoechst 33342) and dead cells (propidium iodide) every 24 h for 5 days using the Cytation 1 Cell Imaging Multi-Mode Reader. RNA sequencing analysis of HUVECs irradiated with 2 Gy and 5 Gy at 24 h and 72 h after IR was conducted, focusing on processes related to EC activation. To validate the RNA sequencing results, immunofluorescence staining for proteins related to EC activation, including Stimulator of Interferon Response cGAMP Interactor 1 (STING), Nuclear factor kappa B (NF-κβ), and Vascular cell adhesion molecule 1 (VCAM-1), was performed. To validate the in vitro results, the response of TEC in vivo was analyzed using publicly available RNA sequencing data of TECs isolated from MC38 colon carcinoma irradiated with a single dose of 15 Gy. Finally, murine CT26 colon carcinoma tumors were immunofluorescently stained for STING and NF-κβ 24 and 48 h after IR with a clinically relevant fractionated regimen of 5 × 5 Gy. Results: Doses of 2, 4, 6, 8, and 10 Gy led to a dose-dependent decrease in proliferation and increased death of ECs. RNA sequencing analysis showed that the effects on the transcriptome of HUVECs were most pronounced 72 h after IR with 5 Gy, with 1014 genes (661 down-regulated and 353 up-regulated) being significantly differentially expressed. Irradiation with 5 Gy resulted in HUVEC activation, with up-regulation of the immune system and extracellular matrix genes, such as STING1 (log₂FC = 0.81) and SELE (log₂FC = 1.09), respectively; and down-regulation of cell cycle markers. Furthermore, IR led to the up-regulation of immune response- and extracellular matrix (ECM)-associated signaling pathways, including NF-κβ signaling and ECM–receptor interaction, which was also observed in the transcriptome of irradiated murine TECs in vivo. This was confirmed at the protein level with higher expressions of the EC activation-associated proteins STING, NF-κβ, and VCAM-1 in irradiated HUVECs and irradiated TECs in vivo. Conclusions: IR induces changes in ECs and TECs, supporting their activation in dose- and time-dependent manners, potentially contributing to the anti-tumor immune response, which may potentially increase the infiltration of immune cells into the tumor and thus, improve the overall efficacy of RT, especially in combination with immune checkpoint inhibitors. Full article

Cancer, a leading global cause of death responsible for nearly 10 million deaths annually, demands innovative therapeutic strategies. Intrinsic cytotoxicity and biocompatibility of zinc oxide nanoparticles (ZnO-NPs) have rendered them promising nanoplatforms in oncology. We herein systematically review their applications for targeted cancer chemotherapy, with a focus on physicochemical properties, drug delivery mechanisms, and interactions with the tumor microenvironment (TME). We searched PubMed, SCOPUS, and Web of Science from inception through December 2024 for peer-reviewed preclinical studies on cancer models. Results were qualitatively synthesized. Quality was assessed with the SYRCLE risk of bias tool. Among 20 eligible studies, ZnO-NPs were frequently functionalized with ligands to enhance tumor targeting and minimize systemic toxicity. Chemotherapeutic agents (doxorubicin, 5-fluorouracil, docetaxel, cisplatin, gemcitabine, and tirapazamine) were loaded into ZnO-based carriers, with improved anticancer efficacy compared to free drug formulations, particularly in multidrug-resistant cell lines and in vivo murine xenografts. The mildly acidic TME was exploited for pH-responsive drug release, premature leakage reduction, and improvement of intratumoral accumulation. Enhanced therapeutic outcomes were attributed to reactive oxygen species generation, zinc ion-mediated cytotoxicity, mitochondrial dysfunction, and efflux pump inhibition. Deep tumor penetration, apoptosis induction, and tumor growth suppression were also reported, with minimal toxicity to healthy tissues. ZnO-NPs might constitute a versatile and promising strategy for targeted cancer chemotherapy, offering synergistic anticancer effects and improved safety profiles. Future studies emphasizing long-term toxicity, immune responses, and scalable production could lead to clinical translation of ZnO-based nanomedicine in oncology. Full article

Melanoma is one of the most aggressive skin cancers, with increasing rates of occurrence. Although it has not traditionally been considered hormonally driven, recent evidence links androgen receptor (AR) signaling to important aspects of melanoma biology, including tumor growth, metastasis, immune evasion, and resistance to therapy. Mechanistically, AR promotes melanoma progression by activating a pro-metastatic gene program, suppressing anti-tumor immune responses, and altering the tumor microenvironment. Additionally, emerging data indicate AR’s involvement in resistance to chemotherapy and immune-based therapies. This review provides a comprehensive overview of AR’s intricate role in melanoma, focusing on its molecular mechanisms, its impact on immune evasion and therapy resistance, and its potential clinical applications. We also assess AR-targeted strategies, including androgen deprivation therapy and AR antagonists, to improve the effectiveness of chemotherapy, targeted therapy, and immunotherapy. Understanding AR’s role in melanoma could lead to new treatment options, particularly for sex-specific patient groups. Full article

Background: Stereotactic ablative radiotherapy (SABR) is increasingly used in the treatment of localized and metastatic renal cell carcinoma (RCC), a malignancy traditionally considered radioresistant. Beyond direct cytotoxicity, SABR may promote immunogenic cell death and modulate the tumor immune microenvironment, though the underlying mechanisms remain incompletely understood. Objectives and Methods: This study examined the immunomodulatory effects of two high-dose irradiation regimens (8 Gy and 3 × 8 Gy) in an in vitro model using two RCC cell lines (ACHN, Caki-2) and peripheral blood mononuclear cells (PBMCs) from healthy donors. Results: The 3 × 8 Gy regimen more effectively reduced tumor cell viability and proliferation, particularly in ACHN cells, suggesting differential radiosensitivity. Both regimens induced secretion of IL-6, IL-8, TGF-β, and VEGF, with levels varying by cell line and dose. Caki-2 cells exhibited a cytokine profile consistent with a pro-inflammatory and potentially immunosuppressive phenotype. Conditioned media from irradiated cells were used to stimulate PBMCs, revealing divergent responses. Media from 3 × 8 Gy-irradiated ACHN cells enhanced PBMC proliferation and increased CD8⁺ T cells and CD11c⁺ monocytes, along with IFN-γ, IL-2, and TNF-α secretion, suggesting immunostimulatory effects. Conversely, media from Caki-2 cells had minimal impact on PBMC proliferation and increased TGF-β levels. Conclusions: These results indicate that high-dose irradiation can differentially modulate immune responses in RCC cell lines, depending on tumor intrinsic properties and irradiation regimen. Further in vivo studies are warranted to validate these findings and support development of SABR immunotherapy combinations guided by predictive immune biomarkers. Full article

Background: Cucurbitacin B (CuB) is a relatively unique and valuable component in plants of the Cucurbitaceae family due to its diverse and remarkable physiological activities, but its specific mechanisms in regulating tumor metabolism and immune response remain unclear. The hypoxic tumor microenvironment (TME) of pancreatic cancer induces metabolic reprogramming in cancer cells, causing them to rely on glycolysis for energy. LDHA, a key enzyme in glycolysis, can suppress glycolysis and tumor growth when inhibited. Objective: The objective of this study was to investigate the mechanism of CuB against pancreatic cancer and its effect on the immune system. Methods: In this study, cell migration/invasion assays, immunofluorescence, ELISA, Western blot, CETSA, flow cytometry, mouse models, and metabolomic and transcriptomic analyses were utilized to systematically elucidate the mechanism by which CuB inhibits pancreatic cancer and activates the immune system. Results: This study confirms that CuB inhibits pancreatic cancer by suppressing the PI3K/Akt/mTOR pathway and activating PINK1/Parkin to induce mitophagy, thereby inhibiting cell migration, invasion, and proliferation. It downregulates the expression of LDHA to block glycolysis, reduce lactate production and efflux, and improve the acidic TME. CuB also induces ICD to activate dendritic cells, promote CD8+ T-cell and M1 macrophage infiltration, and reduce the levels of regulatory T cells. Metabolomic and transcriptomic analyses validate CuB’s dual effects on metabolic reprogramming and immune activation. Conclusions: This study, for the first time, reveals that CuB induces mitophagy via the PI3K/Akt/mTOR and PINK1/Parkin pathways to selectively eliminate damaged mitochondria and suppress tumor energy metabolism. CuB inhibits pancreatic cancer through a triple mechanism—inducing mitophagy, inhibiting glycolysis, and activating immunity—which provides innovative insights for pancreatic cancer therapy. Full article

Background: Ovarian cancer is an immunologically cold tumor that is treated with surgery and a chemotherapy regimen of platinum agents with taxanes. Paradoxically, elevated levels of several immune markers are effective at predicting prognosis for patients with ovarian cancer, though it is not clear how chemotherapy might influence this. Chemotherapy elicits immunogenic cell death, yet tumor-controlling doses of chemotherapy are also immunotoxic. Objectives: To evaluate interactions of chemotherapy with the immune system, we studied the impact of chemotherapy in an aggressive mouse model of ovarian cancer developed within our lab. Methods: Using a single-cell transcriptomics sequencing approach, supported by flow cytometry, we evaluated the influence of a first-line therapy, cisplatin and docetaxel, and a second-line therapy, pegylated liposomal doxorubicin (PLD), on control of tumor growth and on tumor-associated immune populations of cells. Results: Both chemotherapy approaches were effective at controlling tumor growth and selectively depleted tumor cells from distinct transcriptional clusters. Both chemotherapies also resulted in relative increases in immune populations compared to untreated tumor-bearing mice, but immune populations from PLD-treated mice were more abundant and expressed a greater fraction of maturity-associated transcripts and increased proportions of tumor resident macrophage populations. PLD treatment selectively upregulated MHC class II on tumor cells, and this could be replicated in vitro across ovarian cancer cell lines and in patient tumor cells ex vivo. Conclusions: Altogether, the results support the notion that PLD has a greater capacity for immunopotentiation, which may be important to consider if immunotherapy approaches are adapted for ovarian tumors in the future. Full article

Pancreatic ductal adenocarcinoma (PDA) exhibits diverse molecular aberrancies that contribute to its aggressive behaviour and poor patient survival. P-21-activated kinase 1 (PAK1) and PAK4 drive the tumorigenesis of PDA. However, their roles in tumour vasculature and the impact on immune response are unclear. This study aims to investigate the effects of PAK1 and PAK4 on tumour vasculature, immune cell infiltration, and the connection between using PAK1-knockout (KO), PAK4 KO, and wild-type (WT) PDA cells in cell-based and mouse experiments. Tumour tissues isolated from a syngeneic mouse model were immuno-stained to determine the changes in tumour vasculature and immune cell infiltration/activation, followed by a proteomic study to assess biological processes involved. PAK1KO or PAK4KO suppressed tumour growth by reducing angiogenesis while enhancing vascular normalisation, enhanced the infiltration/activation of T-cells and dendritic cells associated with upregulation of ICAM-1 and VCAM-1 in the tumour microenvironment, and stimulated vascular immune crosstalk via an ICAM-1-mediated mechanism. This was supported by proteomic profiles indicating the regulation of endothelial cell and leukocyte trans-endothelial migration in PAK1- or PAK4-knockout tumours. In conclusion, PAK1KO or PAK4KO enhanced tumour vascular normalisation while reducing angiogenesis, stimulating immune cell infiltration and activation to suppress tumour growth. Full article

Biliary tract cancer (BTC) is a rare and aggressive type of malignancy characterized by heterogeneity both in tumor biology and in the immune microenvironment. Most patients are diagnosed with advanced-stage disease and have limited curative options. Although the introduction of immune-checkpoint inhibitors (ICI) has transformed the treatment landscape for several solid tumors, their effects on BTC remain modest. New combinations have promoted incremental improvements in the survival of patients with advanced BTC, but the complex interplay between immune therapies and the tumor microenvironment continues to be a major challenge to improve therapeutic outcomes. Nonetheless, ongoing studies are investigating combinations that may potentially improve results in this lethal disease. This review provides an overview of the evolving role of ICIs in BTC, discusses the impact of tumor heterogeneity on treatment response, and explores future directions to optimize patient selection. Full article

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by chronic inflammation of the synovial membrane, leading to synovial hyperplasia, infiltration of immune cells, and subsequent cartilage and bone erosion. This progressive joint pathology results in persistent pain and functional impairment. Currently, convenient oral traditional disease-modifying anti-rheumatic drugs (DMARDs) are available, and increasingly precise biologic agents and targeted synthetic DMARDs (tsDMARDs) have been developed, offering promising therapeutic options. However, systemic administration generally fails to achieve therapeutic drug concentrations in the joints owing to poor biodistribution and dose-limiting systemic toxicity. Intra-articular (IA) administration has demonstrated promising potential in addressing these challenges. Among the various strategies employed for IA administration, hydrogels have gained significant attention due to their tunable mechanical properties, biocompatibility, and controlled release capabilities. These unique properties enable hydrogel-based IA delivery systems to simultaneously modulate the inflammatory microenvironment and protect cartilage tissue. This review comprehensively summarizes the histopathological changes and associated cellular and molecular events in RA, while also highlighting the design principles of hydrogels and advanced strategies for hydrogel-based IA administration. By addressing the limitations of conventional treatments, hydrogel-based IA injection holds significant promise for improving RA treatment. Full article

Background: Ovarian cancer ranks as the fifth leading cause of cancer-related mortality among women worldwide. Owing to its insidious onset and lack of early symptoms, over 70% of patients are diagnosed at advanced stages. Methods: This study provides a comprehensive transcriptomic analysis of tumor-infiltrating CD4⁺ T cells in ovarian cancer, highlighting regulatory T cells (Tregs) as the dominant subset. By integrating seven multicenter ovarian cancer single-cell RNA-seq datasets, a robust metadata resource was created for detailed Treg investigation. Using the BayesPrism algorithm, Treg scores from TCGA bulk RNA-seq data enabled patient stratification into high and low Treg groups. These findings were further validated through survival analyses across five independent bulk RNA-seq cohorts. We experimentally validated the inhibitory role of Tregs in modulating CD8⁺ T-cell activity in ovarian cancer. Results: We conducted an in-depth investigation into the clustering patterns, differentiation trajectories, intercellular interactions, and enrichment profiles of tumor-infiltrating T cells in ovarian cancer. Among the seven functionally defined subclusters (C1–C7), we delineated two distinct “terminal states” of CD4⁺ T-cell differentiation: FOXP3⁺ regulatory T cells and STMN1⁺ proliferative T cells. The OCSCDs dataset comprises seven datasets totaling 137,648 single cells. Using the TCGA dataset, we quantified the proportion of tumor-infiltrating regulatory T cells (Tregs) in OCSCDs through the BayesPrism algorithm and performed survival analyses across five independent bulk RNA-seq datasets from different platforms. Conclusions: Our results establish a framework for studying Treg biology in ovarian cancer and these cells may be become an important point in the field of immunotherapy. Full article

Despite improved diagnostic and treatment protocols, cancer remains a leading cause of morbidity and mortality globally. There are increasing rates of certain cancer types, including the highly drug-resistant colorectal cancer, in younger population cohorts. Therapeutic advances in oncology have led to the application of immunotherapy-based agents, including checkpoint inhibitors, antibodies, and adoptive cell therapies. Such immunotherapy approaches are greatly hindered by the tumour microenvironment and lack of specificity. Therapeutic vaccines are an innovative and rapidly advancing area of oncology, having potential for application as mono- and combined therapy in clinical settings, offering long term efficacy against disease recurrence. Advances in vaccine production using gene editing and bioprocessing techniques allows for novel vaccine types, including protein-based subunit vaccines, virus-like particle vaccines, and viral vector- and nucleic acid-based (RNA and DNA) vaccines. Cancer vaccines are designed to deliver specific tumour antigens, which activate anti-cancer cytotoxic T cells and helper T cells to produce immune memory, providing long term anti-cancer action. When coupled with advances in machine learning and artificial intelligence, anti-cancer vaccines may revolutionise oncology protocols and improve patient prognosis. This review aims to discuss current immunotherapy options in cancer treatment and recent advances in anti-cancer vaccine modalities. Full article