X‑ray FLASH RT inhibits lung cancer bone metastasis via activating CD4⁺ T-cell‑mediated antitumor immunity with modulation of Th17 cell response

Lung cancer is characterized by rapid progression and poor prognosis, with 50%-70% of patients presenting local or distant metastasis at diagnosis, among which bone metastasis is the most common type. Radiotherapy is the standard approach for managing cancerous bone metastasis pain. Here, we report the first application of X-ray FLASH radiotherapy (RT) in treating lung cancer bone metastasis in mice. Using an intratibial LLC-luc cell injection model, mice were treated with FLASH RT (94 Gy/s) or conventional RT (CONV RT, 0.1 Gy/s) via a petal accelerator developed by the Institute of Fluid Physics, China Academy of Engineering Physics. The results demonstrated that X-ray FLASH RT and CONV RT exhibited comparable efficacy in suppressing tumor growth, and both may alleviate osteolytic lesions in mice with lung cancer bone metastasis through CD4⁺ T cell-dependent antitumor responses. However, FLASH RT further attenuated bone destruction by inhibiting osteoclastogenesis, remodeling the bone-tumor microenvironment, and reducing tumor invasion, with lower systemic toxicity. Notably, unlike CONV RT, FLASH RT instigates a distinct DNA damage response that drives oxygen depletion, thereby attenuating ROS accumulation. This mechanistic cascade sequentially suppresses cGAS-STING-NF-κB axis activation and dampens the ensuing inflammatory response. In addition, we observed a reduction in Th17 cell differentiation following FLASH RT compared to CONV RT, which may contribute to the differential efficacy of these two radiation modalities in attenuating lung cancer bone metastasis. Collectively, X-ray FLASH RT provides a promising therapeutic strategy for patients with bone metastases.