Ionizable Lipid Nanoparticle-Mediated TRAIL mRNA Delivery in the Tumor Microenvironment to Inhibit Colon Cancer Progression

International Journal of Nanomedicine, Journal Year: 2024, Volume and Issue: Volume 19, P. 2655 - 2673

Published: March 1, 2024

Introduction: Immunotherapy has revolutionized cancer treatment by harnessing the immune system to enhance antitumor responses while minimizing off-target effects. Among promising cancer-specific therapies, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) attracted significant attention. Methods: Here, we developed an ionizable lipid nanoparticle (LNP) platform deliver TRAIL mRNA (LNP-TRAIL) directly microenvironment (TME) induce cell death. Our LNP-TRAIL was formulated via microfluidic mixing and induction of death assessed in vitro. Next, investigated ability inhibit colon progression vivo combination with a TME normalization approach using Losartan (Los) or angiotensin 1– 7 (Ang(1– 7)) reduce vascular compression deposition extracellular matrix mice. Results: results demonstrated that induced vitro effectively inhibited vivo, particularly when combined Los Ang(1– 7). In addition, potent as well enhanced apoptosis found tissue group treated normalization. Discussion: Together, our data demonstrate potential LNP death, especially Therefore, these findings provide important insights for development novel therapeutic strategies immunotherapy solid tumors. Keywords: immunotherapy, TRAIL, mRNA, nanoparticle, losartan, (1– 7)

Language: Английский

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Intestinal tissue-resident memory T cells: Characteristics, functions under physiological and pathological conditions and spatial specificity

Journal of Advanced Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Tissue-resident memory T (TRM) cells are a distinct subset of that persist in non-lymphoid tissues, providing localized and rapid immune responses to infection malignancy. Unlike circulating cells, TRM have unique homing functional characteristics shaped by the tissue microenvironment. In gut, play pivotal role maintaining mucosal immunity, exhibiting phenotypic heterogeneity different intestinal compartments response aging pathological conditions. This review aims systematically examine definition, spatial roles (iTRM) cells. It highlights their contributions physiological involvement processes such as inflammatory bowel disease (IBD) colorectal cancer (CRC), age-related dynamics. The also explores emerging therapeutic implications modulating iTRM for health management. KEY SCIENTIFIC CONCEPTS OF REVIEW: defined surface markers like CD69 CD103, transcriptional regulators Hobit, Runx3, Blimp-1, well cytokine signals including TGF-β, IFN-β, IL-12. They exhibit across layers (epithelium versus lamina propria) regions (small intestine colon). IBD, dual role, contributing both inflammation repair, whereas CRC, specific subsets (e.g., CD8+ CD103+ CD39+) associated with enhanced antitumor immunity. Aging impacts functionality, shifts CD4+/CD8+ ratio reduced production elderly individuals. Insights into metabolic, transcriptional, environmental regulation provide avenues targeted therapies diseases, immunotherapy, interventions delay aging.

Language: Английский

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Optimization of Immunotherapy Strategies Based on Spatiotemporal Heterogeneity of Tumour‐Associated Tissue‐Resident Memory T Cells

Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Tissue-resident memory T cells (TRMs) reside in peripheral tissues and provide rapid immune defence against local infection tumours. Tumour-associated TRMs share common tissue-resident features formation mechanisms, representing some unique subsets of tumour-infiltrating lymphocytes (TILs). However, differences the tumour microenvironment(TME) evolution stage result exhibiting temporal spatial heterogeneity phenotype function not only at different stages, before after treatment, but also between tumours originating from tissues, primary metastatic cancer, adjacent normal tissue. The infiltration is often associated with immunotherapy response favourable prognosis; however, due to definitions, it has been shown that subtypes can have a negative impact. Therefore, crucial precisely characterise TRM subpopulations influence therapeutic efficacy clinical prognosis various solid Here, we review spatiotemporal tumour-associated TRMs, as well their impact on outcomes. We explore relationship checkpoint blockade (ICB) TIL therapy, providing insights into potential new targets strategies for immunotherapy.

Language: Английский

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Multifaceted functions of tissue-resident memory T cells in tumorigenesis and cancer immunotherapy

Cancer Immunology Immunotherapy, Journal Year: 2025, Volume and Issue: 74(6)

Published: April 26, 2025

Tissue-resident memory T (TRM) cells are well reported as a strong protective first line of defense against foreign antigens in non-lymphoid tissues. Moreover, TRM have demonstrated critical roles antitumor immunity, contributing to enhanced survival and tumor growth inhibition across various cancer types. However, surprisingly, recent studies suggest that can exhibit paradoxical effects, potentially promoting progression under certain conditions leading adverse outcomes during immune responses. Understanding the complexities cell functions will enable us harness their potential advancing immunotherapy more effectively. Therefore, this review comprehensively investigates dual different contexts, highlighting combating cancers unfavorable exacerbate development. Additionally, we explore implications behaviors for future treatment strategies, emphasizing need further research optimize therapeutic exploitation while mitigating deleterious effects.

Language: Английский

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Does side matter? Deciphering mechanisms that underpin side-dependent pathogenesis and therapy response in colorectal cancer

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: May 2, 2025

Language: Английский

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CD39 transforming cancer therapy by modulating tumor microenvironment

Cancer Letters, Journal Year: 2024, Volume and Issue: 597, P. 217072 - 217072

Published: June 15, 2024

CD39 is a pivotal enzyme in cancer, regulating immune response and tumor progression via extracellular ATP adenosine the microenvironment (TME). Beyond its established immunoregulatory function, influences cancer cell angiogenesis metabolism, opening new frontiers for therapeutic interventions. Current research faces gaps understanding CD39's full impact across types, with ongoing debates about potential beyond modulating evasion. This review distills multifaceted roles, examining dual actions implications prognosis treatment. We analyze latest strategies, highlighting need an integrated approach that combines molecular insights TME dynamics to innovate care. synthesis underscores integral role, charting course precision oncology seeks unravel controversies harness promise improved outcomes.

Language: Английский

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Single-cell transcriptomics and Mendelian randomization reveal LUCAT1’s role in right-sided colorectal cancer risk

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

Published: April 22, 2024

Background: Colorectal cancer (CRC) is a malignancy with high incidence and mortality rates globally, categorized into left-sided right-sided CRC, each exhibiting significant differences in molecular characteristics, clinical manifestations, prognosis. Methods: This study employed single-cell transcriptomic data various bioinformatics approaches, such as two-sample Mendelian randomization, reverse colocalization analysis, directed filtering, pseudotime intercellular communication analysis. It analyzed cellular-level disparities between identifying distinct subpopulations characteristic variations. For these cells, randomization was utilized to explore gene-to-one-sided CRC causality. Results: LUCAT1 enriched high-abundance monocyte demonstrated potential risk factor status through The specific single-nucleotide polymorphism (SNP) rs10774624 associated an increased of CRC. Moreover, metabolic pathway analysis revealed that + monocytes exhibit lower activity the tumor microenvironment heightened functions like glycosaminoglycan degradation. Its biological are related positive regulation interleukin-6 production NF-kappa B signaling, among others. Conclusion: confirmed causal relationship These findings provide novel insights pathogenesis may aid developing early detection treatment strategies for

Language: Английский

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Tissue-Resident Memory T Cells in Gastrointestinal Cancers: Prognostic Significance and Therapeutic Implications

Biomedicines, Journal Year: 2024, Volume and Issue: 12(6), P. 1342 - 1342

Published: June 17, 2024

Gastrointestinal cancers, which include a variety of esophageal and colorectal malignancies, present global health challenge require effective treatment strategies. In the evolving field cancer immunotherapy, tissue-resident memory T cells (Trm cells) have emerged as important players in immune response within nonlymphoid tissues. this review, we summarize characteristics functions Trm discuss their profound implications for patient outcomes gastrointestinal cancers. Positioned strategically peripheral tissues, beyond surveillance, affecting tumor progression, prognosis, to immunotherapy. Studies indicate that are prognostic markers correlate positively with enhanced survival. Their presence microenvironment has sparked interest therapeutic potential, particularly respect checkpoint inhibitors, may improve treatment. Understanding how work will not only help prevent spread through but also contribute disease prevention at early stages well vaccine development. The role goes just cancer, they potential applications infectious autoimmune diseases. This review provides thorough analysis lead personalized therapies.

Language: Английский

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Inhomogeneously distributed ferroptosis with a high peak-to-valley ratio may improve the antitumor immune response

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: Aug. 28, 2023

Combined radiotherapy (RT) and mild hyperthermia have been used clinically for decades to increase local control. Both modalities tend achieve a homogeneous dose distribution within treatment targets induce immunogenic cell death. However, marked, long-lasting abscopal effects not usually observed. We proposed hypothesis emphasize the importance of peak-to-valley ratio inside tumor ferrroptosis in peak area while avoid nonimmunogenic ferroptosis valley area. Although inhomogeneous distributed energy absorption has noted many anticancer medical fields, idea sedulously created inhomogeneity related antitumor immunity discussed. To scale up ratio, we possible implications by combination nanoparticles (NP) with conventional RT or hyperthermia, use high modulation depth extremely low frequency resolution spatially fractionated (SFRT) enhance immune reactions.

Language: Английский

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PEPSI: Polarity measurements from spatial proteomics imaging suggest immune cell engagement

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 17, 2023

Subcellular protein localization is important for understanding functional states of cells, but measuring and quantifying this information can be difficult typically requires high-resolution microscopy. In work, we develop a metric to define surface polarity from immunofluorescence (IF) imaging data use it identify distinct immune cell within tumor microenvironments. We apply characterize over two million cells across 600 patient samples find that identified as having polar expression exhibit characteristics relating tumor-immune engagement. Additionally, show incorporating these polarity-defined subtypes improves the performance deep learning models trained predict survival outcomes. This method provides first look at using subcellular patterns phenotype with applications precision medicine.

Language: Английский

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