GM-CSF and IL-21-armed oncolytic vaccinia virus significantly enhances anti-tumor activity and synergizes with anti-PD1 immunotherapy in pancreatic cancer

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 3, 2025

Pancreatic cancer is one of the most aggressive cancers and poses significant challenges to current therapies because its complex immunosuppressive tumor microenvironment (TME). Oncolytic viruses armed with immunoregulatory molecules are promising strategies overcome limited efficacy target inaccessible metastatic tumors. In this study, we constructed a tumor-selective vaccinia virus (VV) deletions TK A49 genes (VVLΔTKΔA49, VVL-DD) using CRISPR-Cas9-based homologous recombination. VVL-DD exhibited selectivity in vitro anti-tumor potency vivo murine pancreatic model. Then, was an optimal combination immunomodulatory molecules, granulocyte-macrophage colony-stimulating factor (GM-CSF) interleukin-21 (IL-21), produce VVL-GL21. VVL-GL21 induced regression after intratumoral systemic administration. Moreover, increased infiltration dendritic cells (DCs), macrophages, T cells; DC maturation; transition from M2 M1 macrophages; improved formation immune memory; prevented recurrence; effectively bolstered response against tumors multiple key compartments. Interestingly, mice bearing-pancreatic treated showed immunity lung colon Importantly, treatment enhanced responsiveness checkpoint inhibitor anti-PD1. Taken together, remodels suppressive TME has powerful activities as monotherapy or anti-PD1 by delivery for cancer. could be used therapeutic vaccine.

Language: Английский

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Role of glycosylation-related gene MGAT1 in pancreatic ductal adenocarcinoma

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Aug. 1, 2024

pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with very poor prognosis and complex microenvironment, which plays key role in progression treatment resistance. Glycosylation an important processes such as cell signaling, immune response protein stability.

Language: Английский

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Next-generation therapies for pancreatic cancer

Expert Review of Gastroenterology & Hepatology, Journal Year: 2024, Volume and Issue: 18(1-3), P. 55 - 72

Published: Feb. 28, 2024

Introduction Pancreas ductal adenocarcinoma (PDAC) is a frequently lethal malignancy that poses unique therapeutic challenges. The current mainstay of therapy for metastatic PDAC (mPDAC) cytotoxic chemotherapy. NALIRIFOX (liposomal irinotecan, fluorouracil, leucovorin, oxaliplatin) an emerging standard care in the setting. An evolving understanding pathogenesis driving shift toward targeted therapy. Olaparib, poly-ADP-ribose polymerase (PARP) inhibitor, has regulatory approval maintenance BRCA-mutated mPDAC along with other agents receiving disease-agnostic approvals including rare fusions and mismatch repair deficiency. Ongoing research continues to identify evaluate expanding array therapies PDAC.

Language: Английский

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Tumor-penetrating iRGD facilitates penetration of poly(floxuridine-ketal)-based nanomedicine for enhanced pancreatic cancer therapy

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 369, P. 444 - 457

Published: April 6, 2024

Language: Английский

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Precision treatment of pancreatic ductal adenocarcinoma

Cancer Letters, Journal Year: 2024, Volume and Issue: 585, P. 216636 - 216636

Published: Jan. 25, 2024

Language: Английский

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Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via exosomes in gastrointestinal tumors

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: Feb. 23, 2024

Gastrointestinal (GI) tumors are a significant global health threat, with high rates of morbidity and mortality. Exosomes contain various biologically active molecules like nucleic acids, proteins, lipids can serve as messengers for intercellular communication. They play critical roles in the exchange information between tumor cells microenvironment (TME). The TME consists mesenchymal components extracellular matrix (ECM), fibroblasts being most abundant cell type mesenchyme. Cancer-associated (CAFs) derived from normal stem that activated TME. CAFs secrete exosomes to modulate proliferation, invasion, migration, drug resistance, other biological processes tumors. Additionally, manipulate function behavior through direct cell-cell interactions. This review provides summary crosstalk GI exosomes, along potential underlying mechanisms.

Language: Английский

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Overcoming therapy resistance in pancreatic cancer: New insights and future directions

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 229, P. 116492 - 116492

Published: Aug. 15, 2024

Pancreatic adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer deaths by 2030 and this mostly due therapy failure. Limited treatment options resistance standard-of-care (SoC) therapies makes PDAC one types with poorest prognosis survival rates [1,2]. tumors are renowned for their poor response therapeutic interventions including targeted therapies, chemotherapy radiotherapy. Herein, we review hallmarks in current strategies aiming tackle escape mechanisms re-sensitize cells therapy. We will further provide insights on recent advances field drug discovery, nanomedicine, disease models that setting ground future research.

Language: Английский

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The global, regional burden of pancreatic cancer and its attributable risk factors from 1990 to 2021

BMC Cancer, Journal Year: 2025, Volume and Issue: 25(1)

Published: Jan. 31, 2025

Pancreatic cancer is the 12th most common type of cancer, and sixth leading cause cancer-related mortality, worldwide. Up-to-date statistics on pancreatic would provide us with a better understanding epidemiology identify causative risk factors for prevention this disease. The degree change patterns exposure as well attributable burden, including incidence, disability-adjusted life years (DALYs), prevalence in global regional, by sex, age, year, data extracted from Global Burden Diseases Study (GBD) 2021. All analyses were conducted using linear regression analysis Joinpoint software (version 5.0.1). In 2021, 508,533 new cases have been reported; mortality rate increased to 5.95, 5.12 respectively; DALYs 130.33 year. Besides, cancer-associated rates DALYs, higher males than females. addition, these indicators high SDI (Sociodemographic index) region mean. To date, fasting plasma glucose remained major factor that influenced followed tobacco body mass index (BMI). Results study suggest burden increasing generally, therefore, more attention measures should be taken cope situation.

Language: Английский

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Rational Design of Metal–Organic Frameworks for Pancreatic Cancer Therapy: from Machine Learning Screening to In Vivo Efficacy

Advanced Materials, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 2, 2025

Abstract Despite improvements in cancer survival rates, metastatic and surgery‐resistant cancers, such as pancreatic cancer, remain challenging, with poor prognoses limited treatment options. Enhancing drug bioavailability tumors, while minimizing off‐target effects, is crucial. Metal–organic frameworks (MOFs) have emerged promising delivery vehicles owing to their high loading capacity, biocompatibility, functional tunability. However, the vast chemical diversity of MOFs complicates rational design biocompatible materials. This study employed machine learning molecular simulations identify suitable for encapsulating gemcitabine, paclitaxel, SN‐38, identified PCN‐222 an optimal candidate. Following loading, MOF formulations are improved colloidal stability biocompatibility. In vitro studies on cell lines shown cellular internalization, delayed release. Long‐term tests demonstrated a consistent performance over 12 months. vivo tumor‐bearing mice revealed that paclitaxel‐loaded PCN‐222, particularly hydrogel local administration, significantly reduced spread tumor growth compared free drug. These findings underscore potential effective system hard‐to‐treat cancers.

Language: Английский

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5-Hydroxymethylcytosine modifications in circulating cell-free DNA: frontiers of cancer detection, monitoring, and prognostic evaluation

Biomarker Research, Journal Year: 2025, Volume and Issue: 13(1)

Published: March 7, 2025

Abstract Developing accurate, clinically convenient, and non-invasive methods for early cancer detection, monitoring, prognosis assessment is essential improving patient survival rates, enhancing quality of life, reducing the socioeconomic burden associated with cancer. This goal critical in precision oncology. Genetic epigenetic alterations circulating cell-free DNA (cfDNA) have emerged as transformative tools advancing outcomes. Among these, 5-hydroxymethylcytosine (5hmC) modifications cfDNA stand out promising markers, offering insights into initiation, progression, metastasis, across various types, such lung cancer, colorectal hepatocellular carcinoma. review comprehensively explores biology sequencing methodologies 5hmC, emphasizing their potential screening, diagnosis, treatment prognostic assessment. It highlights recent advancements cfDNA-derived 5hmC signatures’ applications, addressing strengths limitations context clinical translation. Furthermore, this outlines key challenges future directions integrating routine practice, facilitating personalized management.

Language: Английский

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