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.

Oral squamous cell carcinoma (OSCC) remains a major global health burden, often diagnosed at advanced stages, with limited survival improvement. Epigenetic dysregulation, particularly promoter hypermethylation, plays a significant role in OSCC pathogenesis. Previous study by Demokan et al. identified Gamma-Aminobutyric Acid Receptor Beta-2 (GABRB2) as a candidate gene subject to methylation-dependent transcriptional silencing. This study aimed to evaluate the methylation and expression profiles of GABRB2 in OSCC and to explore its potential as a diagnostic biomarker. Tissue and serum samples from 48 OSCC patients and 15 healthy controls were analyzed for GABRB2 promoter methylation via quantitative methylation-specific PCR and for gene expression levels via quantitative real-time PCR. Relationships between methylation, expression levels, clinicopathological parameters, and patient outcomes were statistically assessed. GABRB2 promoter hypermethylation was detected in 14.6% of tumor samples, predominantly in floor of the mouth and buccal tumors. Decreased GABRB2 expression was observed in 52.1% of tumor tissues compared to matched-normal tissues, while 22.9% of tumors exhibited increased expression. Methylation-dependent expression loss was confirmed in 71.4% of methylated tumors. Notably, decreased expression and hypermethylation of GABRB2 were correlated with poor prognosis parameters (p < 0.05). ROC analysis showed moderate discrimination for GABRB2 expression in distinguishing tumor from normal tissues (AUC = 0.635, p = 0.022), while serum-based analysis demonstrated poor diagnostic performance. Survival analysis revealed no statistically significant prognostic impact of GABRB2 expression levels (p > 0.05). However, alcohol consumption (p = 0.006) and recurrence developed (p = 0.030) as independent predictors of poor prognosis in multivariate analysis. Our study suggests that there was association between methylation-based expression loss of GABRB2 with OSCC’ subgroups. To our knowledge, this is the first study to investigate GABRB2 gene methylation and expression profiling in both invasive/non-invasive samples from OSCC patients. Hypermethylation in the newly identified candidate GABRB2 gene may play a role in the development of tumors originating from the mouth floor and buccal anatomical regions of the oral cavity. However, since the loss of expression seen in the majority of our patients, we thought that only methylation may not the inhibition mechanism for GABRB2 gene decreased expression. The new identified candidate gene may be specific for the OSCC’s subgroups.

Objective: Pancreatic cancer is the cancer type with the highest mortality rate worldwide, and despite advances in treatment, molecular biomarkers are needed for both early diagnosis for developing targeted therapies and improving survival rates in this challenging malignancy. In our study, the contributions of programmed death-ligand 1 (PD-L1) expression to the determination of pancreatic cancer subtypes and patient prognosis and its impact on survival were investigated. Material and Methods: Paraffin-embedded tissues from 92 patients diagnosed with pancreatic cancer were included in this study. Tumor-infiltrating lymphocytes (TILs) and lymphocytes in the stromal area within the tumor borders were scored as stromal TILs; lymphocytes in tumor islands were scored as intratumoral TILs. Staining in each area was scored as a percentage, and staining with a score of 5 or more in tumor and immune cells for PD-L1 was scored as positive. Results: After staining, a score of 5 or more with tPD-L1 staining was used to identify one patient as having micropapillary adenocarcinoma, three patients as having ductal adenocarcinoma, and four patients as having signet ring cell carcinoma. When the clinical parameters and outcomes were compared, a statistically significant difference was found between the histopathologic type of signet ring cell carcinoma and poor differentiation and positivity of PD-L1 expression (P < 0.05). Survival was significantly influenced by tumor location, histopathological subtype, degree of differentiation, PD-L1 expression, and tumor size, with tumor size being the most critical factor (P < 0.05). Conclusion: Our findings suggest that PD-L1 positivity is notably prevalent in signet ring cell carcinoma of the pancreas and is strongly associated with poor survival outcomes. Given these results, further studies with larger patient cohorts are warranted to validate these observations and explore potential therapeutic implications.

Background/Objectives: Glioblastoma is a highly aggressive brain tumor with limited treatment options and poor prognosis. Signal Transducer and Activator of Transcription 3 (STAT3) plays a crucial role in glioblastoma progression, making it a promising therapeutic target. However, effective delivery of STAT3-silencing agents across the blood–brain barrier remains a significant challenge. This study evaluates the efficacy of Lipid Nanoparticles-EXOSOME COMPLEX STAT3-silencer treatment in reducing glioblastoma tumor growth by facilitating efficient small interfering RNA delivery and inhibiting STAT3 expression. Methods: A novel exosome-based drug delivery system was developed using NLP-EXOSOME COMPLEX nanoparticles loaded with STAT3-silencer siRNA. The therapeutic efficacy was assessed in vitro using human glioblastoma cell lines and in vivo using a glioblastoma mouse model. Tumor progression, STAT3 expression levels, and survival rates were analyzed. Results: The results demonstrated that Lipid Nanoparticles-EXOSOME COMPLEX effectively transported STAT3-silencer siRNA into glioblastoma cells, leading to significant STAT3 downregulation. This resulted in reduced tumor proliferation, increased apoptosis, and extended survival in vivo. The combination of lipid nanoparticles and exosomes provided a stable and efficient delivery mechanism with improved uptake and therapeutic efficacy. Conclusion: Lipid Nanoparticles-EXOSOME COMPLEX STAT3-silencer treatment offers a promising approach for targeted glioblastoma therapy by overcoming the blood–brain barrier limitations and enhancing STAT3 inhibition. Further research is necessary to optimize long-term efficacy, assess potential immune responses, and explore combinatory therapeutic strategies for improved patient outcomes.

Background: Metastatic pancreatic adenocarcinoma carries a dismal prognosis, and treatment options after progression on standard chemotherapy remain limited. We report a metabolic response in a patient with drug-resistant disease treated with a combined multimodal regimen that paired dose-reduced (“activated”) multi-agent chemotherapy with targeted agents and metabolic/microenvironmental support, set against an unusually long overall survival. Case Presentation: A 46-year-old man was diagnosed with inoperable, locally advanced/stage IV pancreatic adenocarcinoma in June 2023 and maintained disease control for approximately 2.5 years on a combined multimodal regimen, termed here metabolically controlled oncologic therapy (MCOT): dose-reduced chemotherapy given with regional hyperthermia, hyperbaric oxygen, and a carbohydrate-restricted diet. In February 2026 he developed local recurrence and diffuse liver metastases, and by May 2026 had deteriorated rapidly, with ¹⁸F-FDG PET/CT showing a peak SUVmax of 18.2 and CA 19-9 of 2788 U/mL. His regimen was intensified to a low-dose, multi-agent “activated” chemotherapy protocol combined with lenvatinib, everolimus, hyperthermia, and hyperbaric oxygen. Clinical Findings and Outcomes: One month later, his performance status had recovered from ECOG PS 2 to PS 0, CA 19-9 was 31 U/mL, and follow-up PET/CT showed a 63.7% decrease in SUVmax (from 18.2 to 6.6). Treatment-related adverse events included Grade 1 nausea, Grade 1 vomiting, and thrombocytopenia; no Grade 2 or higher non-hematological toxicity was observed. Conclusions: In selected patients who are considered to have exhausted standard options, a combined multimodal regimen pairing dose-reduced chemotherapy with metabolic and microenvironmental support may produce a well-tolerated metabolic response. As a single, uncontrolled observation, these findings cannot establish causality and require confirmation in prospective, controlled studies.