Clofazimine enhances anti-PD-1 immunotherapy in glioblastoma by inhibiting Wnt6 signaling and modulating the tumor immune microenvironment

Cancer Immunology Immunotherapy, Journal Year: 2025, Volume and Issue: 74(4)

Published: March 7, 2025

Glioblastoma multiforme (GBM) is an aggressive and lethal primary brain tumor with limitedtreatment options due to its resistance conventional therapies immunosuppressive microenvironment. In this study, we investigated whether clofazimine, inhibitor of the Wnt/β-catenin signaling pathway, could enhance efficacy anti-PD-1 immunotherapy in GBM. Our vitro vivo experiments demonstrated that clofazimine suppressed GBM cell proliferation, induced apoptosis, inhibited invasion by downregulating Wnt6-mediated activation pathway downstream MEK/ERK cascade, leading decreased PD-L1 expression. Notably, combination therapy significantly reduced growth intracranial orthotopic mouse models, resulting extended survival. This also reshaped immune microenvironment increasing cytotoxic CD8+ T infiltration, reducing regulatory cells, promoting receptor clonality diversity, indicative a robust anti-tumor response. findings suggest enhances therapeutic effects through modulation Wnt6/β-catenin/PD-L1 axis reshaping While these results are promising, further clinical studies needed evaluate safety combinatory approach patients.

Language: Английский

Phospholipase D6 activates Wnt/β-catenin signaling through mitochondrial metabolic reprogramming to promote tumorigenesis in colorectal cancer

Experimental & Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: April 21, 2025

Abstract Phospholipase D6 (PLD6) is a critical enzyme involved in mitochondrial fusion with key role spermatogenesis. However, the of PLD6 cancer remains unknown. Notably, Wnt signaling, energy metabolism and function show complex interactions colorectal (CRC) progression. Here we found that highly expressed CRC positively correlated poor prognosis. We present novel activating Wnt/β-catenin signaling by enhancing metabolism. depletion suppresses oncogenic properties cells impairs respiration, leading to reduced length, membrane potential, calcium levels reactive oxygen species. also disrupts metabolic reprogramming inhibiting tricarboxylic acid cycle oxidative phosphorylation, resulting altered intracellular citrate acetyl-CoA—both modulators activation. PLD6-mediated acetyl-CoA production enhances β-catenin stability promoting its acetylation via acetyltransferases CREB-binding protein P300/CREB-binding-protein-associated factor. Consequently, ablation reduces stem cell-associated gene expression downstream suppressing stem-like traits chemoresistance 5-fluorouracil. Furthermore, attenuates tumorigenesis both subcutaneous orthotopic tumor models. Overall, acts as an switch mitochondria-mediated retrograde thereby regulating CRC.

Language: Английский

Meningiomas in Rubinstein-Taybi syndrome: A case report and comprehensive review

Journal of Neuropathology & Experimental Neurology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 31, 2024

Abstract Rubinstein-Taybi syndrome (RTS) is a congenital disorder with characteristic clinical manifestations. In the vast majority of cases, it caused by mutations gene encoding transcriptional co-activator cAMP-response element binding protein (CBP)-binding (CREBBP). It has been thought to be tumor predisposition as RTS patients have an increased risk developing tumors including meningiomas. However, RTS-associated meningiomas are rarely reported. We report unique meningioma in which oncogenic CREBBP mutation identified. also comprehensively review reported meningiomas, from epidemiology and pathogenesis clinicopathological characteristics treatment. All female exclusive CREBBP. population-based studies seem develop at younger ages. Their may driven CREBBP/CBP alterations resulting aberrant signal transduction CBP-mediated signaling pathways. Meningiomas common comorbidity other tumors, radiologically intra-osseous growth, uncommon histopathology such ossifying secretory features. Given genetic nature rarity further investigation their define molecular targets for improved therapeutic options patients.

Language: Английский