High KYNU Expression Is Associated with Poor Prognosis, KEAP1/STK11 Mutations, and Immunosuppressive Metabolism in Patient-Derived but Not Murine Lung Adenocarcinomas DOI Open Access
Ling Cai, Thomas J. Rogers,

Reza Mousavi Jafarabad

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(10), P. 1681 - 1681

Published: May 16, 2025

Background/Objectives: We aimed to discover genes with bimodal expression linked patient outcomes, reveal underlying oncogenotypes and identify new therapeutic insights in lung adenocarcinoma (LUAD). Methods: performed meta-analysis screen LUAD datasets for prognostic patterns. Kynureninase (KYNU), a key enzyme tryptophan catabolism, emerged as top candidate. then examined its relationship mutations, metabolic alterations, immune microenvironment states, patterns human mouse models using bulk single-cell transcriptomics, metabolomics, preclinical model datasets. Pan-cancer associations were also assessed. Results: Model-based clustering of KYNU outperformed median-based dichotomization accuracy. was elevated tumors KEAP1 STK11 co-mutations but remained strong independent marker. Metabolomic analysis showed that KYNU-high had increased anthranilic acid, catalytic product, while maintaining stable kynurenine levels, suggesting compensatory mechanism sustaining immunosuppressive signaling. Single-cell data cancer cell-intrinsic immune-cold myeloid-derived immune-infiltrated tumors. In murine models, Kynu predominantly immune-derived uncoupled from Nrf2/Lkb1 signaling, indicating poor fidelity. KYNU’s extended across types, outcomes pancreatic kidney cancers favorable melanoma, underscoring the need lineage-specific considerations therapy development. Conclusions:KYNU is robust biomarker potential immunometabolic target LUAD, especially co-mutated Its phenotype offer translational potential, though species-specific pose challenges modeling.

Language: Английский

Clinical landscape of macrophage-reprogramming cancer immunotherapies DOI Creative Commons
Jenna H. Rannikko, Maija Hollmén

British Journal of Cancer, Journal Year: 2024, Volume and Issue: 131(4), P. 627 - 640

Published: June 3, 2024

Tumour-associated macrophages (TAMs) sustain a tumour-supporting and immunosuppressive milieu therefore aggravate cancer prognosis. To modify TAM behaviour unlock their anti-tumoural potential, novel TAM-reprogramming immunotherapies are being developed at an accelerating rate. At the same time, scientific discoveries have highlighted more sophisticated phenotypes with complex biological functions contradictory prognostic associations. understand evolving clinical landscape, we reviewed current past clinically evaluated therapeutics summarised almost 200 agents investigated in than 700 trials. Observable overall trends include high frequency of overlapping strategies against therapeutic targets, development to improve previously ineffective approaches reliance on combinatory for efficacy. However, strong anti-tumour efficacy is uncommon, which encourages re-directing efforts identifying biomarkers eligible patient populations comparing similar treatments earlier. Future endeavours will benefit from considering shortcomings treatment accommodating emerging complexity biology.

Language: Английский

Citations

20
RORγt-expressing dendritic cells are functionally versatile and evolutionarily conserved antigen-presenting cells DOI Creative Commons
Hamsa Narasimhan, Maria Lucia Richter, Ramin Shakiba

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(9)

Published: Feb. 24, 2025

Conventional dendritic cells (cDCs) are potent antigen-presenting (APCs) that integrate signals from their environment allowing them to direct situation-adapted immunity. Thereby they harbor great potential for being targeted in vaccination, autoimmunity, and cancer. Here, we use fate mapping, functional analyses, comparative cross-species transcriptomics show RORγt + DCs a conserved, functionally versatile, transcriptionally distinct type of DCs. entail various populations described different contexts including Janus cells/RORγt-expressing extrathymic Aire-expressing (eTACs), subtypes Thetis cells, -DC (R-DC) like cDC2C ACY3 We response inflammatory triggers, can migrate lymph nodes the spleen activate naïve CD4 T cells. These findings expand repertoire beyond known role eTACs inducing cell tolerance self-antigens intestinal microbes mice. further with proinflammatory features accumulate autoimmune neuroinflammation mice men. Thus, our work establishes as immune sentinel exhibit broad spectrum ranging peripheral activation depending on environment.

Language: Английский

Citations

4
Molecular mechanisms and therapeutic significance of Tryptophan Metabolism and signaling in cancer DOI Creative Commons
Jing Yan, Di Chen, Zi Ye

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: Oct. 30, 2024

Language: Английский

Citations

15
New insight into arginine and tryptophan metabolism in macrophage activation during tuberculosis DOI Creative Commons
Kangling Zhang, Abhishek Mishra, Chinnaswamy Jagannath

et al.

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

Published: March 28, 2024

Arginine and tryptophan are pivotal in orchestrating cytokine-driven macrophage polarization immune activation. Specifically, interferon-gamma (IFN-γ) stimulates inducible nitric oxide synthase (iNOS) expression), leading to the conversion of arginine into citrulline (NO), while Interleukin-4 (IL4) promotes arginase activation, shifting metabolism toward ornithine. Concomitantly, IFN-γ triggers indoleamine 2,3-dioxygenase 1 (IDO1) induced (IL4i1), resulting kynurenine indole-3-pyruvic acid. These metabolic pathways tightly regulated by NAD + -dependent sirtuin proteins, with Sirt2 Sirt5 playing integral roles. In this review, we present novel insights that augment our understanding following Mycobacterium tuberculosis infection, particularly their relevance responses. Additionally, discuss methylation demethylation role regulating metabolism, potentially driving polarization.

Language: Английский

Citations

14
Macrophage diversity in cancer dissemination and metastasis DOI Creative Commons
Alberto Mantovani, Federica Marchesi, Diletta Di Mitri

et al.

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(11), P. 1201 - 1214

Published: Oct. 14, 2024

Invasion and metastasis are hallmarks of cancer. In addition to the well-recognized hematogenous lymphatic pathways metastasis, cancer cell dissemination can occur via transcoelomic perineural routes, which typical ovarian pancreatic cancer, respectively. Macrophages a universal major component tumor microenvironment and, in established tumors, promote growth secondary sites. Here, we review role tumor-associated macrophages (TAMs) emphasizing diversity myeloid cells different tissue contexts (lungs, liver, brain, bone, peritoneal cavity, nerves). The generally used models lung fail capture microenvironments. A better understanding TAM may pave way for tailored diagnostic therapeutic approaches.

Language: Английский

Citations

11
Nanomedicines Targeting Metabolic Pathways in the Tumor Microenvironment: Future Perspectives and the Role of AI DOI Creative Commons

Shuai Fan,

Wenyu Wang,

Wieqi Che

et al.

Metabolites, Journal Year: 2025, Volume and Issue: 15(3), P. 201 - 201

Published: March 13, 2025

Background: Tumor cells engage in continuous self-replication by utilizing a large number of resources and capabilities, typically within an aberrant metabolic regulatory network to meet their own demands. This dysregulation leads the formation tumor microenvironment (TME) most solid tumors. Nanomedicines, due unique physicochemical properties, can achieve passive targeting certain tumors through enhanced permeability retention (EPR) effect, or active deliberate design optimization, resulting accumulation TME. The use nanomedicines target critical pathways holds significant promise. However, requires careful selection relevant drugs materials, taking into account multiple factors. traditional trial-and-error process is relatively inefficient. Artificial intelligence (AI) integrate big data evaluate delivery efficiency nanomedicines, thereby assisting nanodrugs. Methods: We have conducted detailed review key papers from databases, such as ScienceDirect, Scopus, Wiley, Web Science, PubMed, focusing on reprogramming, mechanisms action development metabolism, application AI empowering nanomedicines. integrated content present current status research metabolism potential future directions this field. Results: Nanomedicines possess excellent TME which be utilized disrupt cells, including glycolysis, lipid amino acid nucleotide metabolism. disruption selective killing disturbance Extensive has demonstrated that AI-driven methodologies revolutionized nanomedicine development, while concurrently enabling precise identification molecular regulators involved oncogenic reprogramming pathways, catalyzing transformative innovations targeted cancer therapeutics. Conclusions: great Additionally, will accelerate discovery metabolism-related targets, empower optimization help minimize toxicity, providing new paradigm for development.

Language: Английский

Citations

2
Antitumor Effects of Tryptanthrin on Colorectal Cancer by Regulating the Mitogen-Activated Protein Kinase Signaling Pathway and Targeting Topo I and IDO1 DOI Creative Commons

Shing-Hwa Lu,

Bao-Long Hou, Ting Wang

et al.

ACS Omega, Journal Year: 2025, Volume and Issue: 10(3), P. 3206 - 3221

Published: Jan. 10, 2025

Tryptanthrin (TRYP) is an indole quinazoline alkaloid with a range of pharmaceutical activities, but the specific mechanism TRYP against colorectal cancer (CRC) remains obscure. The purpose this study was to evaluate antitumor effects on CRC models both in vitro and vivo further analyze its concrete mechanisms. results experiment show that effectively inhibited proliferation migration SW620 cells, arrested cell cycle at S phase, induced apoptosis. Deeply, dramatically increased expression Bax cleaved caspase 3 while decreasing Bcl-2. transcriptome sequencing implied inhibitory were closely related mitogen-activated protein kinase (MAPK) signaling pathway, western blotting verified could decrease p-Erk increase p-p38 p-Jnk. Besides, our identified topoisomerase I (Topo I) amine 2,3-dioxygenase 1 (IDO1) targets TRYP. In vivo, showed different doses significantly tumor growth mice, degrees necrosis tissues, decreased level Ki67 protein, apoptotic signal tissues. findings demonstrated CRC, mechanisms tightly connected inhibiting activity Topo IDO1 regulating MAPK pathway. Especially, it first directly inhibit arrest phase. Therefore, work established scientific basis for development

Language: Английский

Citations

1
Amino acid metabolism in glioblastoma pathogenesis, immune evasion, and treatment resistance DOI Creative Commons
Shriyansh Srivastava,

Robab Anbiaee,

Mohammad Houshyari

et al.

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

Published: March 13, 2025

Glioblastoma (GBM) ranks among the most lethal primary tumors of central nervous system. This is partly due to its complex intracellular metabolism and interactions with surrounding tumor microenvironment (TME). Compelling evidence represents that altered amino acids (AAs) plays a crucial role in both areas. The AAs their metabolites glioma biology an emerging topic. Therefore, this review was conducted summarize current knowledge about molecular mechanisms by which participate GBM pathogenesis. can directly influence progression affecting cell or indirectly releasing bioactive agents through particular metabolic pathways. begins examining pathways essential AAs, such as tryptophan, tyrosine, phenylalanine, contribute synthesizing critical neurotransmitters shape signatures. We explore how these impact growth immune modulation, focusing on promote malignant properties cells. also play pivotal reprogramming TME, contributing evasion resistance therapy. further discusses signatures, influenced AA metabolism, enhance immunosuppressive microenvironment, providing new avenues for targeted immunotherapies. Finally, we outline potential therapeutic strategies modulate emphasize opportunities future research improve management.

Language: Английский

Citations

1
Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease DOI Creative Commons
Cédric Peleman,

Stig Hellemans,

Geraldine Veeckmans

et al.

Cell Death and Differentiation, Journal Year: 2024, Volume and Issue: 31(9), P. 1113 - 1126

Published: July 26, 2024

There is an unmet clinical need for pharmacologic treatment metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death a hallmark of this highly prevalent chronic disease, but the dominant type remains uncertain. Here we report that ferroptosis, iron-catalyzed mode regulated death, contributes to MASLD. Unsupervised clustering in cohort biopsy-proven MASLD patients revealed subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, reduced defenses was discerned public transcriptomics datasets. Four weeks choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due hepatocyte-specific knockout. The inhibitor UAMC-3203 attenuated steatosis alanine aminotransferase second model, i.e., high-fructose (HFHFD). effect monounsaturated saturated fatty acids supplementation on susceptibility assessed human HepG2 cells. Fat-laden showed drop defenses, increased phosphatidylglycerol two polyunsaturated acid (PUFA) lipid tails, sustained sensitivity. In conclusion, study identified as detrimental factor patients. Unexpectedly, non-PUFA hepatocytes altered bilayer composition maintain Based findings vivo models, inhibition represents promising therapeutic target

Language: Английский

Citations

9
Ferroptosis-based advanced therapies as treatment approaches for metabolic and cardiovascular diseases DOI Creative Commons
Francesca Maremonti, Wulf Tonnus, Shubhangi Gavali

et al.

Cell Death and Differentiation, Journal Year: 2024, Volume and Issue: 31(9), P. 1104 - 1112

Published: July 27, 2024

Ferroptosis has attracted attention throughout the last decade because of its tremendous clinical importance. Here, we review rapidly growing body literature on how inhibition ferroptosis may be harnessed for treatment common diseases, and focus metabolic cardiovascular unmet medical needs. We introduce four classes preclinically established inhibitors (ferrostatins) such as iron chelators, radical trapping agents that function in cytoplasmic compartment, lipophilic antioxidants ninjurin-1 (NINJ1) specific monoclonal antibodies. In contrast to inducers cause serious untoward effects acute kidney tubular necrosis, side effect profile ferrostatins appears limited. also consider a potential itself when several advanced therapies harnessing small-interfering RNA (siRNA)-based approaches are tested. Importantly, trial design is impeded by lack an appropriate biomarker detection serum samples or tissue biopsies. However, discuss favorable scenarios suited anti-ferroptosis trials test first-in-class compounds. conclude targeting exhibits outstanding options but have only begun translate this knowledge into clinically relevant applications.

Language: Английский

Citations

8