Breaking oncometabolites dynamics for next-generation dendritic cells tumor immunotherapy

Project Information

REACT-DC

Grant agreement ID: 101078646

DOI

10.3030/101078646

EC signature date 7 February 2023

Start date 1 July 2023

End date 30 June 2028

Funded under

• European Research Council (ERC)

Total cost

€ 1 500 000,00

EU contribution

€ 1 500 000,00

Coordinated by

UNIVERSITA DEGLI STUDI DI PERUGIA
Italy

Periodic Reporting for period 1 - REACT-DC (Breaking oncometabolites dynamics for next-generation dendritic cells tumor immunotherapy)

Reporting period: 2023-07-01 to 2025-12-31

Summary of the context and overall objectives of the project

Cancer remains one of the greatest health challenges of our time, causing millions of deaths each year. While modern immunotherapies have transformed the treatment of some cancers, many tumors are still able to escape immune control. This is particularly true for aggressive cancers such as sarcomas, which often resist standard therapies and leave patients with very limited treatment options.
A key reason for this failure is that the tumor microenvironment—the complex ecosystem of cells and molecules surrounding a tumor—actively suppresses the immune system. Immune cells that would normally attack cancer are reprogrammed into a dysfunctional state. Among these, dendritic cells play a central role: they are the “sentinels” of the immune system, responsible for activating killer T cells that can eliminate tumors. When dendritic cells are disabled, the immune system loses one of its most powerful weapons.
Recent research suggests that tumors achieve this suppression by releasing metabolites, small molecules that alter the behavior of immune cells. One of the key sensors of these molecules is the aryl hydrocarbon receptor (AhR), a protein inside immune cells that normally helps the body respond to environmental signals. Tumors appear to hijack this pathway to block dendritic cell function. However, which metabolites are responsible, and how exactly they affect dendritic cells, was largely unknown before REACT-DC.
The REACT-DC project was created to fill this gap. Its overall objectives are:
• to identify the tumor-derived metabolites that activate AhR;
• to understand how these molecules reprogram dendritic cells, especially the cDC1 subset that is critical for anti-tumor immunity;
• to develop innovative tools (including precision gene-editing) to block this suppression selectively in dendritic cells;
• to translate discoveries into human cancers, with a focus on sarcomas, where new treatment options are urgently needed.
The expected impact of REACT-DC is twofold. Scientifically, the project will change how we think about the relationship between metabolism and immunity, by showing how tumors use their own “chemical language” to silence the immune system. Clinically, it will open the way for next-generation immunotherapies that protect dendritic cells from suppression, restoring the body’s natural capacity to fight cancer.
The significance of this work lies not only in improving survival prospects for patients with sarcoma and other resistant cancers, but also in establishing a new principle in medicine: that by targeting the metabolic communication between tumors and immune cells, we can design more precise and effective therapies. In this way, REACT-DC contributes directly to Europe’s efforts to reduce the burden of cancer and improve the lives of patients and their families.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In its first two years, REACT-DC has built a cutting-edge research environment to study how cancer reprograms the immune system. The project established advanced platforms including metabolomics, innovative animal models and single-cell technologies. A flagship milestone was the installation of the BD FACSDiscover™ S8 CellView, the first in Italy to unite spectral cytometry and imaging, enabling unprecedented immune cell profiling. In parallel, spatial transcriptomics was introduced to analyse immune activity directly within tumor tissues.
With these tools, the project has begun to clarify how tumor metabolism shapes immunity. REACT-DC has:
• Identified candidate tumor-derived molecules that disrupt dendritic cells, key initiators of anti-cancer responses;
• Uncovered new mechanisms of immune suppression, showing that tumor signals affect both dendritic cell function and development;
• Developed precision gene-editing tools to selectively reprogram dendritic cells, offering proof-of-concept for targeted immunotherapies;
• Validated findings in human systems, including donor-derived immune cells and large public cancer datasets, where the pathways studied associate with poor prognosis in aggressive tumors such as sarcomas.
These achievements already go beyond the state-of-the-art, revealing how tumors disable immune defences and providing innovative approaches to restore protection.
By the end of the project, REACT-DC aims to deliver:
• a map of tumor-derived signals acting on dendritic cells;
• validated molecular targets for next-generation immunotherapies;
• innovative gene-editing tools for immune reprogramming;
• and translational insights from human sarcomas, where treatment options are most limited.
Together, these results will lay the foundation for novel therapies that re-empower the immune system against cancer.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The REACT-DC project has advanced beyond the state of the art by showing how tumor metabolism can reprogram dendritic cells, the immune “sentinels” that trigger anti-cancer responses. While most immunotherapy has focused on surface checkpoints, REACT-DC explores how metabolic signals in the tumor microenvironment weaken immune defences, opening a new frontier in explaining therapy resistance.
A major step forward is the development of innovative tools and platforms. The project installed Italy’s first BD FACSDiscover™ S8 CellView, combining spectral cytometry with imaging to study immune–tumor interactions at single-cell level, and introduced spatial transcriptomics to map immune activity directly in tissues. In addition, precision gene-editing tools were created to act selectively in dendritic cells, offering a novel way to restore their function with minimal off-target effects.
The potential impacts are wide. Scientifically, REACT-DC creates a new paradigm linking tumor metabolism to immune suppression. Clinically, it highlights pathways as targets for next-generation therapies, especially for sarcomas and other aggressive cancers. Technologically, it strengthens Europe’s single-cell and spatial platforms, attracting collaboration. Socially, it supports Europe’s mission against cancer, offering hope to patients and families.
For full uptake, discoveries must be validated in preclinical and humanised models, and clinical partnerships are crucial to design translational studies, particularly in sarcoma. Some tools may also have commercial potential, requiring collaboration with biotech and supportive regulatory frameworks for advanced therapies. International cooperation will further expand impact.
By the end of the project, REACT-DC will deliver a comprehensive picture of how tumor metabolism undermines dendritic cell function, a set of validated molecular targets for therapy, innovative tools to restore immune activity, and human evidence from sarcomas. These outcomes will lay the foundation for future clinical applications, bridging the gap between fundamental discovery and therapeutic innovation, and ensuring that the benefits of ERC-funded research can be translated into tangible advances against cancer.

The figure highlights the project’s main objective