Combining Advanced Radiotherapy Techniques and Immunotherapy: Immunomodulatory Mechanisms and Clinical Prospects

Linsen Zhou¹Qianyi Liu¹Yongze He¹Ying Tang¹Shuotong Liu²Xiaobin Wang¹Shiyan Shen¹Jialin Ji¹Zhen Liu³Xianhu Zeng^3*Jiangping Li^4,5*

• ¹Sichuan University West China School of Medicine, Chengdu, China
• ²Sichuan University West China School of Stomatology, Chengdu, China
• ³Department of Radiotherapy Physics & Technology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
• ⁴West China Hospital, Sichuan University, Chengdu, China
• ⁵Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China

This review systematically explores the mechanisms and clinical prospects of combining advanced radiotherapy techniques—including stereotactic body radiotherapy, FLASH radiotherapy, proton therapy, carbon ion radiotherapy, and spatially fractionated radiotherapy—with immunotherapy. It elucidates how radiotherapy activates systemic antitumor immunity by inducing immunogenic cell death, activating the cGAS–STING pathway, upregulating MHC-I expression, and remodeling the tumor microenvironment. These mechanisms synergize with immune checkpoint inhibitors to enhance both local and systemic tumor control, including the abscopal effect. Compared with conventional radiotherapy, these advanced techniques leverage precise dose distributions, ultra-high dose rates, or the Bragg Peak physical properties to better protect normal tissues, mitigate radiation-induced lymphopenia, and favorably modulate the tumor microenvironment. Although preclinical studies and emerging clinical trials support the feasibility and efficacy of such combinations, further large-scale, well-designed clinical trials are required to validate their optimal application strategies and long-term benefits.