Radiation-induced upregulation of itaconate in macrophages promotes the radioresistance of non-small cell lung cancer by stabilizing NRF2 protein and suppressing immune response.

Radioresistance is one of the important reasons for local recurrence and distant metastasis in non-small cell lung cancer (NSCLC). Itaconate primarily functions as an anti-inflammatory metabolite in macrophages, however, its role in radiotherapy remains to be explored. In this study, we demonstrated that radiation significantly increases itaconate in the tumor microenvironment (TME), which is produced by macrophages. Mechanistically, the NF-κB signaling pathway is rapidly activated in macrophages, which enhances the binding of P65 to the Acod1 promoter region, leading to significantly increased secretion of itaconate. Excessive itaconate alleviates oxidative stress of NSCLC cell lines by stabilizing NRF2 protein. Notably, specifically knocking out Acod1 on myeloid cells enhances the activation of the tumor immune microenvironment in response to radiotherapy, particularly increasing the infiltration and activation of CD8 T cells. Therefore, we propose that targeting Acod1 could be an effective strategy to improve radiosensitivity in NSCLC.