Metabolomic reprogramming of the tumor microenvironment by dual arginase inhibitor OATD-02 boosts anticancer immunity
Metabolic reprogramming within the tumor microenvironment (TME) plays a central role in cancer progression and immune evasion, with L-arginine metabolism emerging as a key regulatory axis. Arginase overexpression depletes intratumoral L-arginine, thus suppressing T-cell proliferation while fuelling...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
28 May 2025
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| In: |
Scientific reports
Year: 2025, Jahrgang: 15, Pages: 1-16 |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-025-03446-1 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41598-025-03446-1 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41598-025-03446-1 
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| Verfasserangaben: | Marcin Mikołaj Grzybowski, Yasemin Uçal, Angelika Muchowicz, Tomasz Rejczak, Agnieszka Kikulska, Katarzyna Maria Głuchowska, Małgorzata Szostakowska-Rodzoś, Agnieszka Zagożdżon, Tobias Bausbacher, Agnieszka Tkaczyk, Magdalena Kulma, Paulina Pomper, Michał Mlącki, Adam Konrad Jagielski, Roman Błaszczyk, Carsten Hopf & Zbigniew Zasłona |
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| 245 | 1 | 0 | |a Metabolomic reprogramming of the tumor microenvironment by dual arginase inhibitor OATD-02 boosts anticancer immunity |c Marcin Mikołaj Grzybowski, Yasemin Uçal, Angelika Muchowicz, Tomasz Rejczak, Agnieszka Kikulska, Katarzyna Maria Głuchowska, Małgorzata Szostakowska-Rodzoś, Agnieszka Zagożdżon, Tobias Bausbacher, Agnieszka Tkaczyk, Magdalena Kulma, Paulina Pomper, Michał Mlącki, Adam Konrad Jagielski, Roman Błaszczyk, Carsten Hopf & Zbigniew Zasłona |
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| 520 | |a Metabolic reprogramming within the tumor microenvironment (TME) plays a central role in cancer progression and immune evasion, with L-arginine metabolism emerging as a key regulatory axis. Arginase overexpression depletes intratumoral L-arginine, thus suppressing T-cell proliferation while fuelling tumor growth through polyamine biosynthesis. OATD-02, a novel dual arginase (ARG1/ARG2) inhibitor, reprograms tumor metabolism by restoring L-arginine availability and reducing the levels of polyamines, thereby shifting the TME toward a more immunostimulatory state. Unlike ARG1-selective inhibitors with limited intracellular uptake, OATD-02 effectively inhibits both extracellular and intracellular arginases, thereby addressing a major limitation of first-generation arginase inhibitors. To visualize the pharmacodynamic effects of OATD-02 dosing in mice with spatial resolution, we employed MALDI mass spectrometry imaging (MALDI-MSI), thus enabling direct mapping of metabolic changes within tumor tissues. In preclinical models, OATD-02 treatment led to widespread accumulation of intratumoral L-arginine with concomitant depletion of polyamines and resulted in metabolic shifts that correlated with increased immune cell infiltration and an improved response to immune checkpoint blockade. These findings underscore the role of dual arginase inhibition in reshaping tumor metabolism and overcoming immune suppression by restoring the metabolic fitness of immune cells to fight cancer. The metabolic changes caused by OATD-02 treatment resulted in significantly enhanced antitumor immune responses, increased T-cell infiltration in tumors, expansion of CD8⁺ T cells in draining lymph nodes, and systemic upregulation of T-cell activation markers. These effects translated into a substantial survival benefit in the CT26 tumor model, particularly when combined with anti-PD-1 therapy, where OATD-02 improved checkpoint blockade efficacy by relieving metabolic constraints affecting tumor-infiltrating lymphocytes. By leveraging the unique capabilities of MALDI-MSI, this study provides high-resolution metabolic insights into the mechanism of action of OATD-02, reinforcing its potential as a next-generation metabolic-immunotherapeutic agent. The observed metabolic reprogramming, coupled with enhanced immune activation and prolonged survival, supports the clinical development of OATD-02 as a promising strategy for enhancing cancer immunotherapy efficacy. OATD-02 is currently undergoing clinical evaluation in a phase I/II trial (NCT05759923), which will further elucidate its safety and therapeutic impact. These findings highlight the potential of arginase-targeted therapies in cancer treatment and underscore the value of MALDI-MSI as a powerful tool for tracking metabolic responses to therapy. | ||
| 650 | 4 | |a Cancer imaging | |
| 650 | 4 | |a Cancer immunotherapy | |
| 650 | 4 | |a Cancer metabolism | |
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| 650 | 4 | |a Drug development | |
| 650 | 4 | |a Pharmaceutics | |
| 650 | 4 | |a Target validation | |
| 650 | 4 | |a Tumour immunology | |
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| 700 | 1 | |a Tkaczyk, Agnieszka |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Mlącki, Michał |e VerfasserIn |4 aut | |
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