Our work from the five past years has significantly contributed to the advancement of knowledge in the field of carbon ion radiobiology. We demonstrated their superior relative biological effectiveness (RBE) at different levels: - Gene and chromosomal damage induced by carbon irradiation are so complex that they cannot be transmitted in the progeny of irradiated tumor cells, thus limiting genomic instability and improving local control. Chromosome/chromatid loss appears as a specific signature of carbon ion exposure in sensitive and resistant head and neck squamous cell carcinoma (HNSCC) cells (Hanot et al. Plos One, 2012). We also demonstrated that the response to carbon ions is independent of the telomeres’ size. The presence of long telomeres in tumor cells of patients with glioblastoma is a well-known factor of poor prognosis as they become more resistant to oxidative stress induced by conventional radiotherapy. Thus, our data first underlines that patients with long telomeres can advantageously benefit from carbon-therapy (Ferrandon et al., Mol Neurobiol, 2013). - Cell death is triggered earlier and more significantly by carbon ions in HNSCC or glioblastoma cellular models. It involves either early apoptosis in radiosensitive cells or mitotic catastrophe followed by late apoptosis in radioresistant ones. Apoptosis is activated through a pathway independent of p53, but dependent on ceramide (a lipid signaling mediator) (Alphonse et al, BMC Cancer, 2013; Ferrandon et al., Cancer Letters, 2015), giving carbon ions a significant advantage since 50% of tumors have a mutated p53 gene. - Carbon ions are more effective than photons in killing cancer stem cells (CSCs) in HNSCC. Their association with cell cycle arrest inhibitors or gadolinium-based nanoparticles also increases the efficiency of therapeutic response (Bertrand et al., Stem Cell Rev, 2014; in preparation). Furthermore, molecular connections between the stem-cell state and epithelio-mesenchymal transition (EMT) program have recently emerged, pointing out a double danger for cancer patients since CSCs have the ability to renew indefinitely and are resistant to apoptosis. Our last investigations point out a significant decrease in the migration and invasion of both parental and CSC populations irradiated with carbon ions, thus highlighting the great interest of carbon-therapy in the prevention of recurrences and metastases. Supported by LabEx PRIMES ANR-11-LABX-0063/ANR-11-IDEX-0007, France Hadron ANR-11-INBS-0007, Lyric and CPER ETOILE