Cancer Cell, Journal Year: 2024, Volume and Issue: 43(1), P. 8 - 10
Published: Dec. 12, 2024
Language: Английский
ONCOLOGIE, Journal Year: 2024, Volume and Issue: 26(4), P. 493 - 507
Published: July 1, 2024
Language: Английский
Citations
6
EMBO Reports, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 9, 2025
Abstract Cytotoxic lymphocytes are crucial to our immune system, primarily eliminating virus-infected or cancerous cells via perforin/granzyme killing. Perforin forms transmembrane pores in the plasma membrane, allowing granzymes enter target cell cytosol and trigger apoptosis. The prowess of cytotoxic efficiently eradicate has been widely harnessed immunotherapies against haematological cancers. Despite efforts achieve a similar outcome solid tumours, immunosuppressive acidic tumour microenvironment poses persistent obstacle. Using different types effector cells, including therapeutically relevant anti-CD19 CAR T we demonstrate that pH typically found tumours hinders efficacy therapies by impeding perforin pore formation within immunological synapse. A nanometre-scale study purified recombinant undergoing oligomerization reveals is inhibited specifically preventing β-barrel. absence directly prevents death. This finding uncovers novel layer inhibition must be considered development effective for tumours.
Language: Английский
Citations
0
Published: Jan. 30, 2025
The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the role glycolytic enzymes in Tregs identified phosphoglycerate mutase (PGAM) as being differentially overexpressed associated with highly phenotype. Pharmacologic or genetic inhibition PGAM reduced Treg function while reciprocally inducing markers pro-inflammatory, helper 17 (Th17)-like state. was dependent contribution 3-phosphoglycerate (3PG), substrate, to de novo serine synthesis. Blocking synthesis from 3PG reversed effect polarization, exogenous directly inhibited polarization. Additionally, altering levels vivo serine/glycine-free diet increased peripheral attenuated autoimmunity murine model multiple sclerosis. Mechanistically, found that limits polarization contributing one-carbon metabolism methylation Treg-associated genes. Inhibiting both vitro autoimmune colitis. Our study identifies novel physiologic highlights interconnectivity between glycolysis, synthesis, metabolism, epigenetic regulation function.
Language: Английский
Citations
0
Published: Jan. 30, 2025
The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the role glycolytic enzymes in Tregs identified phosphoglycerate mutase (PGAM) as being differentially overexpressed associated with highly phenotype. Pharmacologic or genetic inhibition PGAM reduced Treg function while reciprocally inducing markers pro-inflammatory, helper 17 (Th17)-like state. was dependent contribution 3-phosphoglycerate (3PG), substrate, to de novo serine synthesis. Blocking synthesis from 3PG reversed effect polarization, exogenous directly inhibited polarization. Additionally, altering levels vivo serine/glycine-free diet increased peripheral attenuated autoimmunity murine model multiple sclerosis. Mechanistically, found that limits polarization contributing one-carbon metabolism methylation Treg-associated genes. Inhibiting both vitro autoimmune colitis. Our study identifies novel physiologic highlights interconnectivity between glycolysis, synthesis, metabolism, epigenetic regulation function.
Language: Английский
Citations
0
Cell Reports Medicine, Journal Year: 2025, Volume and Issue: 6(3), P. 102021 - 102021
Published: March 1, 2025
Constant tumor antigen exposure disrupts chimeric receptor (CAR) T cell metabolism, limiting their persistence and anti-tumor efficacy. To address this, we develop metabolically reprogrammed CAR (MCAR) cells with enhanced autophagy mitophagy. A compound screening identifies a synergy between GLP-1R agonist (semaglutide [SG]) Urolithin (UrA), which activate through mTOR (mechanistic target of rapamycin) inhibition mitophagy via Atg4b activation, maintaining mitochondrial metabolism in (MCAR T-1). These changes increase CD8+ memory (Tm), enhancing activity vitro xenograft models. knockdown diminishes autophagy/mitophagy induction, confirming its critical role. We further engineer GLP-1-secreting T-2), exhibited sustained memory, stemness, long-term persistence, even under re-challenge. MCAR T-2 also reduce cytokine release syndrome (CRS) risks while demonstrating potent effects. This strategy highlights the potential metabolic reprogramming targeting pathways to improve therapy outcomes, ensuring durability
Language: Английский
Citations
0
The Lancet Rheumatology, Journal Year: 2025, Volume and Issue: unknown
Published: March 1, 2025
Language: Английский
Citations
0
Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16
Published: May 2, 2025
Acute myeloid leukemia (AML) is a heterogeneously primary hematopoietic neoplasm characterized by uncontrolled proliferation of immature cells, which with poor outcomes. Despite tremendous advances in the treatment paradigm AML past several decades, cure and prognosis remain unfavorable. More effective treatments are therefore needed to improve clinical Among newly emerging immunotherapies, chimeric antigen receptor (CAR)-T cell immunotherapy an exceedingly promising approach that has remarkably improved overall survival for patients AML. However, current CAR-T therapy faces numerous significant challenges such as identification truly AML-specific surface antigens, on-target/off-tumor toxicity, immunosuppressive microenvironment In order conquer these limitations, novel strategies advance urgently needed. this comprehensive review, we summarize status immunotherapy, especially therapy, highlight outcomes trials limitations hopefully provide insights into future directions cells
Language: Английский
Citations
0
Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: unknown, P. 108763 - 108763
Published: Nov. 1, 2024
Language: Английский
Citations
2
Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: unknown
Published: Dec. 12, 2024
Language: Английский
Citations
2
Journal of Cellular Physiology, Journal Year: 2024, Volume and Issue: 240(1)
Published: Sept. 26, 2024
Abstract Mitochondria are pivotal contributors to cancer mechanisms due their homeostatic and pathological roles in cellular bioenergetics, biosynthesis, metabolism, signaling, survival. During transformation tumor initiation, mitochondrial function is often disrupted by oncogenic mutations, leading a metabolic profile distinct from precursor cells. In this review, we focus on hepatocellular carcinoma, arising metabolically robust nutrient rich hepatocytes, discuss the mechanistic impact of altered metabolism setting. We provide distinctions between normal activity versus disease‐related which yielded therapeutic opportunities, along with highlighting recent preclinical clinical efforts focused targeting metabolism. Finally, several novel strategies for exploiting programs eliminate carcinoma cells metabolism‐specific contexts presented integrate these concepts gain foresight into future mitochondria‐focused therapeutics.
Language: Английский
Citations
1