Search Results (65,696)

Background/Objectives: Lipid nanoparticles (LNPs) have emerged as crucial vehicles for messenger RNA (mRNA) applications in antitumor therapy. Combining LNPs with stimulator of interferon genes (STING) activation holds promise for treating “cold” tumors such as pancreatic cancer. However, two major challenges remain: inefficient mRNA escape from endosomes and STING pathway suppression in immunosuppressive tumor microenvironments. Methods: To improve endosomal escape, we developed a novel pH-responsive PEGylated lipid (Ben-mPEG₂₀₀₀) for mRNA-LNP preparation while using commercial Man-mPEG₂₀₀₀ for dendritic cell (DC)-targeted delivery of LNPs; to alleviate suppression of the STING pathway in the tumor microenvironment and activate immune responses, STING-R283S mRNA was encapsulated into LNPs, ultimately resulting in DC-targeted/pH-responsive LNPs loaded with STING-R283S mRNA for pancreatic cancer immunotherapy research. Results: After pH-responsive cleavage, Ben-mPEG₂₀₀₀ not only enhanced the positive charge of LNPs through the exposed protonated amino groups but also eliminated the PEG-induced steric hindrance effect. The combination of these two effects promoted membrane fusion between LNPs and the endosome, thereby enhancing mRNA translation. As a payload, STING-R283S could further amplify STING signaling in DCs without cytotoxicity to counteract immunosuppression in pancreatic cancer. Conclusions: This engineered LNP platform enhanced mRNA expression and STING activation in DCs, improving immunotherapy outcomes in pancreatic cancer. Full article

Current 3D tumor models for aggressive breast cancers inadequately recapitulate the native tumor microenvironment (TME), leading to poor translational potential. There is a critical need for models capable of mimicking the unique biochemical signals present in the TME. To address this gap, breast tissue and a patient-derived xenograft tumor were decellularized and processed to produce breast tissue- and tumor-specific decellularized extracellular matrices (dECM). Histology confirmed complete cellular removal while maintaining the ECM. Further, DNA content was significantly reduced while ECM composition (POSTN, COLI, FN1) was retained. Breast dECM was incorporated (0, 5, 10, 20, and 50 µg/mL) with triple-negative breast cancer cell lines to generate spheroids. Imaging and histology demonstrated that cells in low dECM (5 and 10 µg/mL) formed compact singular spheres, while higher dECM concentrations (20 and 50 µg/mL) resulted in cells concentrated on the outer edge of the sphere and irregular sphere circularity. RNA-sequencing of MDA-MB-231 dECM spheres demonstrated that gene changes were mediated by both the inclusion of dECM and its composition. High-density tumor dECM upregulated genes associated with metastasis, while high-density breast dECM enhanced tumor suppressors and anti-metastasis genes. These findings indicate that dECM provides physiological cues in 3D tumor models by incorporating TME. Full article

Retroviruses, after their genomes are integrated into the host genome, replicate through host cell replication. In this hitchhiking phase, their only way of increasing their fitness is to encourage the host cell to have unregulated, rapid cell replication. The v-Src gene in avian sarcoma virus and the v-sis gene in the simian sarcoma virus were originally mined from the host genome by the virus to increase host cell replication rate, with the corresponding host cellular counterparts c-Src (non-receptor tyrosine kinase) and c-sis (platelet-derived growth factor). The resulting out-of-control replication ultimately would lead to cancer. The battle between the host and the retroviruses left many retroviral corpses known as endogenous retroviruses, and the host occasionally domesticates retroviral genes. The syncytins (whose fusogenic function is crucial for the trophoblast fusion and the formation of a syncytium during placenta morphogenesis) and suppressyn (which serves the dual function of regulating syncytialization and host resistance against retroviruses) are examples of successful domestication. Syncytin-1 and suppressyn have each been “domesticated” independently multiple times by different mammalian lineages. Molecular phylogenetics is an essential tool for tracing the evolutionary trajectories of such genetic exchanges between retroviruses and their hosts and for determining the direction of the genetic exchange. Full article

Background/Objectives: Triple-negative breast cancer (TNBC) remains a highly aggressive malignancy with limited therapeutic options due to the absence of well-defined molecular targets. Diet-induced obesity (DIO) promotes TNBC progression by reshaping systemic metabolism and inflammatory responses; however, the key circulating metabolites involved and their mechanisms remain largely unclear. This study aimed to identify key metabolites associated with TNBC progression and further investigate their biological functions and molecular mechanisms. Methods: Targeted metabolomics profiling was performed on serum samples from MMTV-PyMT spontaneous breast cancer mice to identify differential metabolites associated with DIO. Functional assays were conducted to evaluate the effects of hippuric acid on TNBC cell proliferation, migration, and invasion. RNA sequencing was conducted to explore downstream regulatory pathways, followed by validation of candidate targets using gain- and loss-of-function approaches as well as rescue experiments. Results: Hippuric acid was identified as a significantly altered metabolite in DIO conditions. Functional studies demonstrated that hippuric acid markedly inhibited the proliferation, migration, and invasion of TNBC cells, with minimal effects on non-TNBC cells. Transcriptomic analysis identified EGFL8 as a potential downstream target, which was further confirmed by qPCR and functional assays. Overexpression of EGFL8 suppressed malignant phenotypes, whereas its knockdown promoted tumor progression. Rescue experiments showed that EGFL8 partially mitigated the inhibitory effects of hippuric acid on TNBC, suggesting that it functions as an important mediator in this process. Mechanistically, hippuric acid exerted its anti-tumor effects at least in part through modulation of the EGFL8-Notch signaling axis. Conclusions: Hippuric acid suppresses TNBC progression via the EGFL8-Notch signaling pathway. These findings highlight a previously unrecognized role of a gut microbiota-derived metabolite in TNBC and suggest its potential as a therapeutic candidate, providing new prospective targets and a theoretical basis for metabolic intervention for TNBC. Full article

Immunotherapy has transformed cancer treatment; however, clinical benefit remains limited to a subset of patients, underscoring the need for robust biomarkers that capture tumor-immune interactions across cancer types. In this study, we performed a comprehensive pan-cancer, multi-omics characterization of the immune checkpoint–related molecules CD70, CD80, and TIGIT to evaluate their diagnostic, prognostic, and immunological relevance. Using integrative analyses of transcriptomic, epigenomic, genomic, pharmacogenomic, and single-cell RNA-sequencing data from The Cancer Genome Atlas and complementary resources, we assessed expression patterns, DNA methylation, somatic mutations, copy number alterations, immune infiltration, tumor stemness, and drug sensitivity. CD70, CD80, and TIGIT were broadly dysregulated across multiple malignancies, with coordinated overexpression particularly evident in kidney renal clear-cell carcinoma. Elevated expression of these immune checkpoints was associated with advanced tumor stage, aggressive molecular subtypes, and unfavorable survival outcomes in selected cancers, including uveal melanoma and renal malignancies. Functional analyses revealed significant associations between checkpoint expression and key oncogenic pathways, including epithelial–mesenchymal transition, apoptosis, and hormone receptor signaling, suggesting links with tumor progression and immune activation states. Immune deconvolution analyses indicated that TIGIT expression is associated with a T-cell–inflamed microenvironment and reduced neutrophil infiltration, while CD80 exhibited methylation-dependent associations with immune cell composition. Genomic and epigenetic alterations were found to correlate with checkpoint expression patterns and immune phenotypes across tumor types. Pharmacogenomic profiling identified associations between checkpoint expression and sensitivity to multiple anticancer agents; however, these findings are based on cell line datasets and should be considered predictive. Single-cell transcriptomic analyses further resolved cell-type–specific expression patterns, distinguishing tumor-intrinsic from immune-restricted expression profiles. Collectively, our findings establish CD70, CD80, and TIGIT as integrative biomarkers of tumor progression, immune contexture, and therapeutic response, providing a rationale for their clinical exploitation in precision immuno-oncology. Full article

This study elucidates the multi-targeted antineoplastic mechanisms of Parkia speciosa empty pod extract (PSET) against HCT-116 and HT-29 colorectal cancer (CRC) cells through integrated transcriptomic and proteomic analyses. Phytochemical profiling indicates that PSET is rich in bioactive metabolites, notably quercetin, rutin, and pyrogallol, which orchestrate its profound ability to inhibit tumor proliferation, migration, and invasion. Transcriptomic data revealed that PSET profoundly suppresses the oncogenic Wnt/β-catenin signaling axis while simultaneously activating p53-mediated cell cycle arrest. Complementary proteomic profiling uncovered critical metabolic vulnerabilities, demonstrating that PSET abrogates the Warburg effect by disrupting key glycolytic enzymes (e.g., ENO1, GAPDH, LDHA), thereby inducing metabolic starvation. Furthermore, the extract precipitated a catastrophic collapse of the cytoskeletal architecture and downregulated epithelial–mesenchymal transition (EMT) markers, effectively paralyzing the cells’ metastatic machinery. The integrated transcriptomic and proteomic signatures also highlighted an irrecoverable state of cellular stress, characterized by an overwhelming unfolded protein response and dysregulated RNA splicing, ultimately driving the cells toward apoptosis. In conclusion, this integrated omics approach provides robust molecular validation that PSET systemically dismantles colorectal cancer survival networks, highlighting its strong potential as a natural, multi-targeted therapeutic agent. Full article

Background/Objectives: Gallic acid (GA) is a naturally occurring polyphenol with reported antioxidant and anticancer properties. This study investigated whether GA enhances carboplatin (CARB)-associated anticancer activity in HeLa cervical cancer cells through mechanisms related to oxidative stress, mitochondrial dysfunction, apoptosis, and cell cycle dysregulation, while comparatively evaluating cytotoxicity in HaCaT cells. Methods: The effects of GA and CARB, individually and in combination, were evaluated using cell viability assays, apoptosis and cell cycle analyses, intracellular reactive oxygen species (ROS) measurements, N-acetylcysteine (NAC)-mediated rescue experiments, mitochondrial membrane potential assessment, reverse transcription–quantitative polymerase chain reaction (RT-qPCR), immunocytochemistry, and three-dimensional (3D) tumor spheroid models. Bioinformatic analyses were performed to explore pathways associated with the observed molecular responses. Results: The GA + CARB combination demonstrated enhanced cytotoxicity and apoptotic activity in HeLa cells compared with either monotherapy, while exhibiting comparatively lower toxicity in HaCaT cells. Combination treatment increased intracellular ROS levels, whereas NAC pretreatment partially reversed ROS accumulation and cytotoxicity, supporting a contributory role of oxidative stress in treatment-associated responses. The combination also induced mitochondrial membrane depolarization, increased G2/M arrest and SubG1 accumulation, and modulated apoptosis- and cell cycle-related gene expression. In 3D spheroid models, GA + CARB reduced spheroid growth and viability and disrupted spheroid integrity more effectively than single-agent treatments. Bioinformatic analyses identified interconnected pathways associated with oxidative stress, apoptosis, and cell cycle regulation. Conclusions: GA may enhance CARB-associated anticancer activity through mechanisms linked to oxidative stress, mitochondrial dysfunction, apoptosis, and cell cycle dysregulation. The incorporation of ROS/NAC rescue experiments and 3D spheroid validation further supports the biological relevance of the observed effects. Nevertheless, these findings remain preliminary and require confirmation in advanced in vivo and translational cervical cancer models. Full article

Background/Objectives: Despite widespread antiretroviral therapy (ART) use, whether the expected transition from AIDS-defining to non-AIDS-defining cancers has occurred in settings with persistent late HIV presentation remains unclear. We examined long-term cancer patterns, determinants, and survival outcomes in a large HIV cohort. Methods: This retrospective, single-center cohort included 1419 people living with HIV followed between 2006 and 2024. Patients who developed malignancy were classified as AIDS-defining cancers (ADC) or non-AIDS-defining cancers (NADC). Immuno-virological parameters were assessed at HIV and cancer diagnosis. Survival was analyzed using Kaplan–Meier methods, and predictors of mortality were evaluated using Cox proportional hazards regression. Determinants of ADC development were assessed using multivariable logistic regression. Temporal changes were evaluated by trend analysis. Results: Sixty-six patients (4.6%) developed malignancy (31 ADC, 35 NADC). Late HIV presentation was common, with 72.7% having CD4+ T-lymphocyte counts < 350 cells/mm³ at cancer diagnosis, particularly among ADC cases. Most ADCs (93.5%) occurred within 24 months of HIV diagnosis. Overall survival did not differ between ADC and NADC groups (log-rank p = 0.14). Although mortality declined after 2015, temporal changes in ADC and NADC proportions did not reach statistical significance (p = 0.14). In Cox regression analysis, viral suppression before death or last follow-up was independently associated with lower mortality risk (HR 0.12; 95% CI 0.05–0.31). Lower CD4+ T-lymphocyte counts were associated with ADC development, and a CD4+ T-lymphocyte threshold of 295 cells/mm³ showed good discriminative performance (AUC = 0.83), although this cutoff should be interpreted cautiously due to the lack of external validation. Conclusions: In this long-term cohort from Türkiye, a clear epidemiological transition from ADC to NADC could not be demonstrated. The cancer spectrum remained strongly influenced by late HIV presentation and advanced immunodeficiency. Sustained viral suppression was independently associated with lower mortality risk, supporting the importance of early HIV diagnosis, timely ART initiation, and sustained virological control. Full article

Background/Objectives: Cervical cancer is mainly driven by persistent infection with high-risk human papillomaviruses (HPV), particularly HPV16 and HPV18. Despite advances in cytology, HPV-DNA testing and vaccination, challenges remain in the triage of HPV-positive individuals, prognostic stratification and prediction of treatment response. Non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs and circular RNAs, together with host genetic factors influencing ncRNA expression and emerging lncRNA-encoded peptides, are increasingly recognized as regulators of HPV-associated carcinogenesis. This review summarizes their biological and potential clinical relevance. Methods: A structured literature search was conducted in PubMed and Scopus. Eligible studies included experimental, clinical, observational, genomic and translational investigations on ncRNA dysregulation, circulating or exosomal ncRNAs, treatment-response signatures, host genetic variation and lncRNA-encoded peptides in HPV-associated cervical precancer and cancer. Results: HPV oncoproteins can reshape host ncRNA networks through transcriptional and epigenetic mechanisms. Several miRNAs, lncRNAs and circRNAs are involved in cell-cycle control, apoptosis, senescence, epithelial–mesenchymal transition, immune regulation, DNA repair and treatment resistance. Circulating, exosomal and urinary ncRNA signatures have shown diagnostic or prognostic potential in exploratory cohorts. Specific lncRNAs, including ENSG00000267838/lnc-LENG9-5 and lncRNA-EME1, have been associated with chemoradiotherapy response and radioresistance. The lncRNA-encoded peptide TUBORF represents a novel preclinical therapeutic candidate, while genetic variation may further modulate lncRNA function in HPV-related cervical cancer. Conclusions: ncRNAs are promising candidates for risk stratification, non-invasive diagnosis, treatment-response prediction and therapeutic development in HPV-associated cervical disease. However, evidence remains exploratory, requiring prospective multicentre validation and standardized workflows before clinical implementation. Full article

Background/Objectives: Clinical studies of prostate cancer treated with radically hypofractionated high-dose-rate brachytherapy (HDR-BT) have reported a significant loss of tumor control that contradicts the standard linear-quadratic (LQ) and low-$\alpha /\beta$-ratio paradigm for prostate cancer. In a previous study by our group, we showed that the linear–quadratic–linear (LQL) model could describe this response, but the underlying biological drivers remained unclear. In this follow-up study, we further investigate whether the interplay between hypoxia and reoxygenation kinetics can explain the poor response to extreme hypofractionation. Methods: We analyzed a large dataset of 3239 patients (44 schedules) using a three-compartment reoxygenation model (the MSK model) that simulates the dynamics of oxic, intermediate, and hypoxic cell populations. Results: The results show that the MSK model achieves an excellent fit to the clinical data ($p>0.99$) while maintaining a biologically plausible low $\alpha /\beta$ ratio (≤8 Gy). The reoxygenation model provided a performance comparable to the LQL model for low-risk prostate cancer and slightly inferior for intermediate-risk. Conclusions: This suggests that the observed reduction in tumor control may not necessarily be a failure of the LQ formalism but, rather, a consequence of oxygen dynamics associated with ultra-hypofractionated schedules. Nonetheless, neither this nor our previous work can provide insight into the driving mechanism and should only be interpreted as showing that both hypotheses are compatible with the clinical data. Full article

Oncogenic viruses are responsible for between 12% and 20% of human cancers worldwide. They trigger tumorigenesis by integrating into host-cell genomes, altering cell cycle pathways, and evading immune detection. Oncoviral cancers exhibit low rates of mutation, implicating alternative splicing as an underappreciated alternative mechanism for oncogene and oncogenic pathway activation in oncoviral pathogenesis and progression. In order to create alternatively spliced viral proteins for replication and viral genome maintenance, oncoviruses take advantage of host-cell splicing machinery. Some of these proteins inhibit major host-cell tumor suppressors to promote the proliferation of DNA-damaged host-cells in order to facilitate persistent infection, whilst others interact with and de-regulate the expression and activity of host-cell splicing factors to alter host transcript splice site selection. The latter reprograms host-cell transcriptomes to express aberrant, sometimes oncogenic protein isoforms, which interact with oncoviral proteins to promote host-cell transformation and subsequent tumor progression to metastatic disease. In this article, we review oncovirus-induced alternative splicing as a fundamental, underappreciated, oncogenic and tumor-promoting mechanism. We compare how different oncoviruses hijack host-cell splicing mechanisms and how specific aberrant alternatively spliced host-cell protein isoforms, induced by different oncoviruses, influence tumor pathogenesis and progression, organized with respect to the hallmarks of cancer. We follow this with more detailed descriptions of each individual oncovirus and a section on therapeutic perspectives. This approach not only crystallizes the complexity of how oncovirus-induced host-cell alternative splicing can influence cancer pathogenesis and progression but also reveals novel potential therapeutic opportunities. Full article

Protein arginine methyltransferase 5 (PRMT5) mediates arginine methylation of a wide range of proteins and plays context-dependent oncogenic or tumor-suppressive roles. In cancer, PRMT5 represses several tumor suppressor genes, including E-cadherin, TP53BP1, ST7, PTEN, and RB (retinoblastoma). Elevated PRMT5 expression has been reported across multiple cancer types, notably triple-negative breast cancer (TNBC). In TNBC, high PRMT5 levels are associated with enhanced cancer stem cell self-renewal, increased tumor growth and metastasis, and reduced patient survival. Mechanistically, PRMT5 promotes breast cancer stem cell maintenance and proliferation through stabilization of the transcription factors KLF4 and KLF5. Disruption of the PRMT5–KLF4 axis results in significant tumor reduction in TNBC models. Moreover, increased PRMT5 expression has been linked to resistance to chemotherapy and immunotherapy in TNBC. Notably, PRMT5 inhibitors demonstrate synergistic anticancer activity when combined with inhibitors of key oncogenic signaling pathways, including EGFR, PARP, and AKT. While several PRMT5 inhibitors are currently being evaluated in clinical trials for other malignancies, no clinical trials have yet been initiated specifically for TNBC. Full article

Growth hormone-releasing hormone (GHRH) antagonists have displayed anti-neoplastic activity against a multitude of cancers in vitro, as well as in vivo, via xenografted tumors in nude mice. Following a successful demonstration of GHRH antagonists treating non-Hodgkin’s lymphoma and the discovery of GHRH mRNA and peptide products in immune cells, GHRH antagonism was explored in acute myeloid leukemia (AML), a disease characterized by a malignant expansion of immature myeloid progenitors, and poor 5-year survival. Targeted therapies have yielded breakthroughs in treatment response and overall survival, such as all-trans retinoic acid/arsenic trioxide (ATRA/ATO) for acute promyelocytic leukemia (APL), or FLT3 inhibitors, IDH inhibitors, and menin inhibitors for AML harboring actionable genetic lesions. However, therapeutic resistance remains a major barrier to durable remission. GHRH receptor (GHRH-R) has been reported in several experimental models of AML, including drug-resistant sublines. Significant time- and dose-dependent reduction in leukemic growth was observed in vitro and in vivo following MIA-602 treatment. FLT3 inhibitor resistance has been associated with activation of PI3K/AKT, ERK/MAPK, inflammatory, stromal, and apoptotic escape pathways. The documented effects of GHRH-R antagonism raise the possibility that it could influence signaling networks relevant to therapeutic resistance in AML. This hypothesis remains speculative; to date no studies have stratified AML by FLT3 status in the context of GHRH-R expression or GHRH antagonism, and there is currently no evidence that MIA-602 directly alters FLT3 receptor signaling or inhibitor sensitivity. Full article

Background/Objectives: Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with a 40% recurrence rate. However, reliable biomarkers for early recurrence detection or treatment guidance are lacking, especially for virus-negative tumors. Circulating tumor DNA (ctDNA), a fragment of tumor-derived cell-free DNA in blood, has emerged across multiple cancers as a minimally invasive precision biomarker to detect minimal residual disease (MRD); predict recurrence; and monitor treatment response. This review’s objective was to summarize recent advances in ctDNA as a tool for therapeutic decision-making in MCC, contextualized by findings in other malignancies. Methods: A comprehensive literature review was performed, focusing on studies published between 2016 and 2026 that evaluate ctDNA in MCC and other cancers. Key prospective trials, observational studies, and case reports were identified through PubMed and relevant conference proceedings. Data on ctDNA assay methods (tumor-informed vs. tumor-agnostic), clinical sensitivity, lead time for recurrence detection, and predictive value for therapy response were extracted and synthesized. Results: Across cancers such as colorectal, lung, and melanoma, ctDNA positivity after curative treatment predicts relapse months in advance of imaging and can guide adjuvant therapy decisions. In MCC, recent studies demonstrate that ctDNA levels correlate with MCC tumor burden and exhibit high sensitivity and specificity for clinically evident disease. Stage I-III MCC patients who were ctDNA-positive within four months of treatment had a 7.4-fold higher recurrence risk within the subsequent 12–18 months of follow-up. Serial ctDNA monitoring may enable earlier intervention in otherwise asymptomatic ctDNA-positive MCC cases, helping distinguish responders from non-responders. Conclusions: ctDNA is an emerging precision biomarker that offers significant prognostic and surveillance utility in MCC. It enables earlier detection of recurrence, potentially allowing treatment to begin before clinical disease manifests. It also helps stratify patients by risk and treatment response, informing personalized surveillance intensity and therapeutic choices. Integrating ctDNA monitoring into MCC management could improve outcomes by guiding timely interventions, although prospective trials are needed to confirm that ctDNA-guided decisions translate to improved patient survival. Formal cost-effectiveness analyses have not yet been conducted and represent an important area for future investigation. Full article