Fig. 1

Radiation therapy can expose immunogenic mutations for MHC-I presentation on the surface of cancer cells. In response to DNA damage that is caused by radiation, double-stranded DNA (dsDNA) accumulates in the cytosol, where it triggers a cellular response similar to that induced by a viral infection. Cytosolic dsDNA binds to cyclic GMP-AMP synthase (cGAS), stimulating the production of cGAMP (cyclic guanosine monophosphate–adenosine monophosphate), which activates Stimulator of interferon genes (STING). Downstream of STING the type I interferon (IFN-I) and NF-κB pathways are activated, resulting in the production of IFN-β and other pro-inflammatory cytokines and in the induction of IFN-stimulated genes, including immunoproteasome subunits. The expression of multiple genes encoding proteins that are involved in DNA damage repair and cell-cycle regulation is also induced. These genes frequently contain mutations. After translation, the mutated proteins will be processed by the (immuno)proteasome and degraded into shorter peptides (8–11 amino acids long) that will enter the endoplasmic reticulum via the transporter associated with antigen processing (TAP) complex. Peptides that bind to MHC-I molecules with sufficient affinity will then be presented at the tumor cell surface, where they can be recognized by CD8 T cells. RT radiotherapy, TCR T-cell receptor