CD38-mediated metabolic reprogramming promotes the stability and suppressive function of regulatory T cells in tumor

Science Advances, Journal Year: 2025, Volume and Issue: 11(12)

Published: March 21, 2025

In the tumor microenvironment (TME), regulatory T cells (T regs ) adapt their metabolism to thrive in low-glucose, high-lactate conditions, but mechanisms remain unclear. Our study identifies CD38 as a key regulator of this adaptation by depleting nicotinamide adenine dinucleotide (oxidized form) (NAD + ), redirecting lactate-derived pyruvate toward phosphoenolpyruvate and bypassing tricarboxylic acid (TCA) cycle. This prevents accumulation α-ketoglutarate, which destabilizes inducing hypermethylation at Foxp3 locus. Restoring NAD with mononucleotide reverses adaptation, pushing back TCA cycle reducing suppressive function. YUMM1.7 melanoma-bearing mice, small-molecule inhibition selectively intratumoral , sparking robust antitumor immunity. These findings reveal that targeting CD38-NAD axis disrupts metabolic offers strategy enhance responses.

Language: Английский

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Development of Multifunctional Targeted Dual-Loaded Polymeric Nanoparticles for Triple-Negative Breast Cancer Treatment

Pharmaceutics, Journal Year: 2025, Volume and Issue: 17(4), P. 425 - 425

Published: March 27, 2025

Background/Objectives: Triple-negative breast cancer (TNBC) is a subtype of that accounts for 15–20% all cases. TNBC very difficult to treat with conventional treatment modalities such as chemotherapy, radiotherapy, and surgery; Methods: In this study, we developed dual-loaded targeted nanotherapeutics against solve the challenging problems associated treatment: lack efficacy, toxicity, poor site-specific drug delivery; PEGylated methacrylate–polylactide copolymer containing cisplatin was synthesized characterized; Results: The used fabricate nanoparticles (NPs) in presence paclitaxel 1.33% loading. were homogenous, an average particle size 198 nm negative zeta potential (−41.3 mV). Cetuximab (CTX), monoclonal antibody binds epidermal growth factor receptor (EGFR), attached NP’s surface enhance targetability TNBC. vitro studies including cell uptake cytotoxicity MDA-MB-231 cells confirmed CTX-targeted NPs have treating IC50 CTX-NPs after 96 h incubation 0.1 μM, which significantly lower than those p-NPs (0.49 μM) free drugs (PTX + cPt: 0.57 μM); Conclusions: summary, research shows polymeric are effective vivo investigations ongoing.

Language: Английский

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Identification of CD38^high Monocyte as a Candidate Diagnostic Biomarker and Therapeutic Target for Sepsis

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

Published: March 27, 2025

Abstract Sepsis is characterized by a systemic host response to infection. Monocytes, as major mediators of acute infection, are implicated in complications among critically ill patients. Identifying key monocyte subsets and their activation states essential for diagnosis delineating new therapeutic targets sepsis. Here, single cell transcriptome sequencing mass cytometry used assess alterations the composition function peripheral monocytes patients with sepsis, CD38 high circulation specifically accumulated within first 24 h detectable conventional flow discriminate sepsis sterile inflammation, associated 28‐day mortality bacterial Targeting therapy markedly reduces inflammatory primary mice model. Mechanistically, exhibit hyperactivated glycolysis hypoxia‐inducible factor‐1α (HIF‐1α) due NAD + consumption. Glycolytic metabolite methylglyoxal (MGO) found regulate expression CD38, establishing CD38‐HIF‐1α/glycolysis/MGO loop that exacerbates sepsis‐induced immune dysregulation. These findings demonstrate might serve candidate diagnostic biomarker target

Language: Английский

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KLRG1 identifies regulatory T cells with mitochondrial alterations that accumulate with aging

Nature Aging, Journal Year: 2025, Volume and Issue: unknown

Published: April 30, 2025

Recent studies using single-cell RNA sequencing technology have uncovered several subpopulations of CD4+ T cells that accumulate with aging. These age-associated are emerging as relevant players in the onset inflammaging and tissue senescence. Here, based on information provided by data, we present a flow cytometry panel allows identification cell subsets systematic larger analysis mice. We use this to evaluate at level mitochondrial senescence marks different subpopulations. Our identifies subpopulation regulatory (Treg) is characterized extracellular expression co-inhibitory molecule killer lectin-like receptor subfamily G member 1 (KLRG1) accumulates aging humans KLRG1-expressing Treg display features such alterations, increased cell-cycle regulators genomic DNA damage. Functionally, KLRG1+ show reduced suppressive activity vivo accompanied pro-inflammatory phenotype.

Language: Английский

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Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 14, 2024

A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% patients metastatic melanoma 1,2 . T cell exhaustion, resulting from chronic antigen exposure tumour microenvironment, a major driver ICB resistance 3 Here, we show that CD38, an ecto-enzyme involved nicotinamide adenine dinucleotide (NAD + ) catabolism, highly expressed exhausted CD8 cells and associated resistance. Tumour-derived CD38 hi are dysfunctional, characterised by impaired proliferative capacity, effector function, dysregulated mitochondrial bioenergetics. Genetic pharmacological murine patient-derived organotypic models (MDOTS/PDOTS) enhanced immunity overcame Mechanistically, disrupting activity restored cellular NAD pools, improved increased proliferation, augmented sensitivity. Taken together, these data demonstrate role for CD38-NAD axis promoting exhaustion establish efficacy directed therapeutic strategies to overcome using clinically relevant, 3D models.

Language: Английский

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