Ionizing radiation has historically been used to treat cancer by killing tumour cells, in particular by inducing DNA damage. This view of radiotherapy (RT) as a simple cytotoxic agent has dramatically changed in recent years, and it is now widely accepted that RT can deeply reshape the tumour environment by modulating the immune response. Such evidence gives a strong rationale for the use of immunomodulators to boost the therapeutic value of RT, introducing the era of ‘immunoradiotherapy’. The increasing amount of preclinical and clinical data concerning the combination of RT with immunomodulators, in particular with immune checkpoint inhibitors such as anti‐PD‐1/PD‐L1 and anti‐CTLA4, reflects the interest of the scientific and medical community concerning immunoradiotherapy. The expectations are enormous since the rationale for performing such combinations is strong, with the possibility to use a local treatment such as RT to amplify a systemic antitumour response, as illustrated by the case of the abscopal effect. Nevertheless, several points remain to be addressed such as the need to find biomarkers to identify patients who will benefit from immunoradiotherapy, the identification of the best sequences/schedules for combination with immunomodulators and mechanisms to overcome resistance. Additionally, the effects of immunoradiotherapy on healthy tissues and related toxicity remain largely unexplored. To answer these critical questions and make immunoradiotherapy keep its promising qualities, large efforts are needed from both the pharmaceutical industry and academic/governmental research. Moreover, because of the work of both these entities, the arsenal of available immunomodulators is quickly expanding, thus opening the field to increasing combinations with RT. We thus forecast that the field of immunoradiotherapy will further expand in the coming years, and it needs to be supported by appropriate investment plans.

The nucleotide-binding oligomerization domain-containing protein 2 (NOD2) agonist muramyl dipeptide (MDP), a peptidoglycan motif common to all bacteria, supports leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) ⁺ intestinal stem cell (ISC) survival through NOD2 activation upon an otherwise lethal oxidative stress-mediated signal. However, the underlying protective mechanisms remain unknown. Here, using irradiation as stressor and primarily murine-derived intestinal organoids as a model system, we show that MDP induced a significant reduction of total and mitochondrial reactive oxygen species (ROS) within ISCs, which was associated with mitophagy induction. ATG16L1 knockout (KO) and NOD2 KO organoids did not benefit from the MDP-induced cytoprotection. We confirmed the MDP-dependent induction of ISC mitophagy upon stress in vivo. These findings elucidate the NOD2-mediated mechanism of cytoprotection involving the clearance of the lethal excess of ROS molecules through mitophagy, triggered by the coordinated activation of NOD2 and ATG16L1 by a nuclear factor κB (NF-κB)-independent pathway.