Targeting STING-ATM axis overcomes radiotherapy-induced immune suppression and restores anti-tumor immunity in nasopharyngeal carcinoma

Background Radiotherapy (RT) is a standard treatment for nasopharyngeal carcinoma (NPC), however, RT-induced immune suppression and tumor radioresistance limit durable cancer control, with approximately 20% of patients developing recurrence or metastasis after treatment. We investigated the molecular effects of RT on the immune landscape of NPC and identified a key role of the STING-ATM-MPO axis in RT-induced immune suppression, which is associated with regulatory T cell (Treg) expansion and radioresistance. Methods We analyzed leukocyte counts from 653 NPC patients before treatment and at multiple time points (week 1-2, week 3-4, and week 5-6) after RT. Single-cell RNA sequencing (scRNA-seq) was performed on peripheral blood mononuclear cell (PBMC) samples from stage I NPC patients (T1N0M0) treated with RT alone. Blood samples were collected before and after 18 Gy RT (in 2 Gy fractions). A randomized six-arm syngeneic mouse tumor model and in vitro cell studies were used to investigate interactions among STING-ATM signaling, immune modulation, and tumor response. Results In NPC patients, RT suppressed cGAS-STING signaling in monocytes and dendritic cells but promoted immunosuppressive programs, including PD-1 signaling, checkpoint expression, regulatory T cell expansion, and upregulation of TGFβ1, IL-10, VEGF, PDGF, and MDSC-associated pathways. In a syngeneic mouse model, co-treatment with the STING agonist diABZI reversed these effects and improved tumor control. Bulk RNA sequencing confirmed that RT suppressed cGAS-STING and ATM signaling in both spleens and tumors. Combination treatment restored this signaling, enhanced neutrophil degranulation, and inhibited PD-1 signaling and immune checkpoints. Immunohistochemistry showed that diABZI increased ATM activation, MPO expression, and reduced Treg infiltration in spleens and tumors. ATM activation correlated positively with MPO and inversely with FOXP3 immunoreactivity, suggesting that STING-ATM-MPO activation counteracts Treg-mediated immune suppression. In vitro, diABZI activated STING-ATM signaling in PBMCs, THP-1 cells, and Jurkat T cells, while inhibiting NPC cell growth partly via CYLD upregulation. Conclusions These findings link RT-induced suppression to inhibition of cGAS-STING signaling. Activation of STING-ATM-MPO axis counteracts Treg-mediated immune suppression, supporting the therapeutic potential of STING agonists as radiosensitizers in NPC.