FLASH radiotherapy preserves systemic and tissue homeostasis while maintaining antitumor efficacy.

BACKGROUND

Conventional radiotherapy (CONV-RT) is widely used for cancer treatment, but its efficacy is limited by toxicity to surrounding healthy tissues. Ultra-high dose rate radiotherapy (FLASH-RT) has emerged as a promising approach, maintaining tumor control while sparing normal tissues. Melanoma is highly radioresistant, and deep-seated lesions expose skin and muscle to radiation, causing long-term fibrosis, stiffness, and loss of elasticity. The aim of this study is to compare the efficacy and collateral effects of CONV-RT and FLASH-RT, using melanoma as a benchmark for tumor response and skin-muscle as a model for normal tissue toxicity, and to investigate the underlying molecular and systemic mechanisms.

METHODS

A novel linear accelerator (LINAC) delivering low-energy electrons at ultra-high dose rate via a triode gun with precise tissue targeting and dose delivery was used. CONV-RT and FLASH-RT were administered to a syngeneic melanoma mouse model. Tumor growth, skin and muscle integrity, transcriptional changes, and systemic homeostasis were analyzed in tumor-bearing and naïve mice.

RESULTS

Both modalities achieved comparable tumor suppression. CONV-RT induced persistent skin damage, dermal fibrosis, muscle dysfunction, and systemic inflammatory-metabolic alterations, whereas FLASH-RT largely preserved tissue architecture and systemic balance. Bulk RNA sequencing revealed minimal transcriptional disruption after FLASH-RT, while CONV-RT triggered thousands of differentially expressed genes, including pathways related to fibrosis, inflammation, cell death in skin, and muscle remodeling, function, and the unfolded protein response. Histological and ultrastructural analyses confirmed reduced immune infiltration and preserved tissue structure following FLASH-RT.

CONCLUSIONS

FLASH-RT provides effective tumor control while largely preserving normal tissues. CONV-RT and FLASH-RT elicit substantially different biological responses, suggesting the involvement of upstream modulators that vary depending on the dose rate.