During the Hadrontherapy for Life symposium held in March 2025 in Caen, France, leading international experts outlined how particle therapy can overcome radioresistance, improve tumor control, and spare healthy tissues, driven by advanced in hypoxia targeting, FLASH irradiation, combination approaches, and integrated preclinical-clinical research.
Advancing particle therapy requires a clear focus on how high-LET ions such as carbon and helium reshape radiobiological responses, enabling improved control of hypoxic and radioresistant tumors.
Current research priorities include characterizing immune-enhancing effects, optimizing healthy-tissue sparing approaches like carbon FLASH, and strenghtening translational workflows. Building better models and integrating clinical and biological expertise will be esssentiel to guide the next generation of particle-therapy strategies.
Radiotherapy can shape systemic antitumor immune responses and combining it with immunotherapy enhances treatment efficacy.
Radiotherapy not only kills cancer cells but also releases signals that reshape the tumor microenvironment, recruit immune cells, and prime T-cell responses. This can over come tumor-induced immuno suppression and improve the effectiveness of check point inhibitors.
Optimizing radiation dose, timing, and understanding patient immune phenotypes is crucial, while particle therapy adds opportunities through unique DNA damage patterns, potentially enhancing immuno genic cell death and supporting a more robust systemic anti tumor immune response.
Tumor hypoxia remains a major challenge in radio therapy, reducing local control and long-term prognosis by promoting radio and chemoresistance, as well as metastatic potential.
Hadrontherapy, particularly with carbon-ions, offers high relative clinical effectiveness in hypoxic tumors compared with photons, especially in hypofractionate schedules.
While carbon ions partially mitigate the impact to flow oxygen, persistent hypoxia still limits effectiveness, highlighting the need for optimized fractionation, imaging-guided planning, and combined strategies to fully exploit particle therapy advantages in hypoxic tumors.
Carbon ions expert distinct radiobiological effects through the combined "bombard" and "stealth" mechanisms :
- The bombard effect induce complex, difficult-to-repair DNA damage, kills cancer stem cells, and operates independently of oxygen levels, making it effective against radioresistant and hypoxic tumors.
- The stealth effect occurs because much of the cell volume is not directly hit, preventing activation of stress and defensive pathways that can trigger adverse such as invasion, migration or angiogenesis.
Together, these mechanisms enhance tumor control while minimizing off-target responses. Preclinical models also show that carbon ions increase immunogenic cell death, supporting synergistic effects with immunotherapy and highlighting their superior potential compared with photons or protons for treating aggressive, resistant cancers.
GSI, GERMANY - Walter Tiganelli
Ongoing research in hadrontherapyfocuses on preclinical radiobiology and the development of innovative treatment strategies.
One key area is carbon FLASH, an ultra-high dose rate irradiation that can control tumors while sparing healthy tissue. Studies are also investigating its effects on metastasis formation and immune response.
These efforts aim to optimize tumor control, reduce side effects, and advance more effective therapies for radioresistantcancers.
HIT, GERMANY - Ivana Dokic
Current research in hadrontherapyexplores how different ion beams (protons, helium, carbon, and oxygen) can overcome tumor radioresistance.
Studies show that higher LET beams induce more complex DNA damage, efficiently target hypoxic and invasive tumor niches, and enhance immune responses. Researchers are also investigating ultra-high dose rate FLASH irradiation, which spares healthy tissue while maintaining tumor control. Preclinical work includes in vitro models, patient-derived organoids, and in vivo studies, aiming to optimize therapies for aggressive and radioresistantcancers.
CNAO, ITALY - Angelica Facoetti
The clinical hadrontherapyfacility includes a dedicated radiobiology unit investigating the biological effects of protons, carbon, helium, and oxygen ions.
Research focuses on tumor radioresistance, DNA damage complexity, and radiation effects on the tumor microenvironment using in vitro models, organoids, spheroids, and in vivo experiments.
Being integrated within the clinical setting enables close collaboration with physicians, facilitates rapid translation of findings, and allows experimental designs that inform patient treatment strategies while supporting external research collaborations.
MedAustron, AUSTRIA - Piero Fossati
Preclinical research is conducted in a dedicated experimental room with the same beam delivery and verification systems as the clinic, supporting physics, biophysics, and radiobiology studies, including cell and small animal experiments with protons and carbon ions.
A key focus is improving translation from biology to clinical practice, for example by studying tumor hypoxia and reoxygenation, and the immunogenic effects of carbon ions, to better guide patient treatment.
QST, JAPAN - Takashi Shimokawa
The institute operates two synchrotrons for clinical treatment and basic research, with dedicated physics and biological radiation rooms.
The research group collaborates closely with physical and biological teams on topics such as FLASH, multi-ion beams, minibeamradiotherapy, regrowingtumor characterization, and non-cancer applications.
University of Caen, FRANCE - Siamak Haghdoost
Three labs focus on overcoming tumor resistance, integrating hadrontherapywith targeted treatments, and evaluating effects on healthy tissue. Research spans clinical, preclinical, and in vitro studies, including hypoxia, DNA repair inhibitors, and proton delivery techniques.
Non-cancer applications include investigating effects on bone marrow, adipose-derived stem cells, and healthy organoids.
A pediatric biobankstudies biomarkers for long-term radiotherapy effects, such as second cancers and chronic inflammation.
Experts discussed current challenges and future strategies in particle radiobiology, with a focus on collaboration, infrastructure, and translational relevance.
They reviewed preclinical research models including in vitro, ex vivo, and in vivo approaches, and explored strategies to support university research programs as well as educational and training opportunities for the next generation of radiobiologists and clinicians.
The session highlighted the importance of strategic planning, funding, and collaboration to advance particle therapy research and ultimately improve patient outcomes.
Watch the full video to explore the discussion and insights on advancing particle therapy research.
The Symposium Hadrontherapyfor Life was recorded in Caen, Normandy –in collaboration with the University of Caen-Normandy, CYCLHAD, François BaclesseCancer Center, Normandy Hadrontherapy(NHa), RégionNormandieand IBA.
The statements of the healthcare professionals included in these videos reflect only their opinion and personal experience. Theydo not necessarily reflect the opinion of any institution with whom they are affiliated or CYCLHAD.
