Targeting Radiotherapy-Induced Inflammation in Cancer Metastasis: Insights into Immune Modulation, Therapeutic Opportunities and Radiogenomics

Ee Qian Lee¹Chin-King Looi²Lu Ping Tan³Yik Ling Chew¹Wei Meng Lim⁴Lian Chee Foong⁵Chee-Onn Leong⁶Kok Whye Cheong¹Chun-Wai Mai^2*

• ¹UCSI University, Cheras, Malaysia
• ²Institute for Research, Development and Innovation, IMU University, Bukit Jalil, Kuala Lumpur, Malaysia
• ³Institute for Medical Research, Shah Alam, Malaysia
• ⁴Monash University Malaysia, Bandar Sunway, Malaysia
• ⁵Shanghai Jiao Tong University, Shanghai, China
• ⁶AGTC Genomics Sdn Bhd, Kuala Lumpur, Malaysia

Radiotherapy (RT) is the first-line treatment for more than 50% of newly diagnosed cancer patients and remains a cornerstone of cancer therapy, particularly for tumors that are inoperable, recurrent, or incompletely resected. Despite advancements in RT techniques, locoregional recurrence and distant metastasis remain critical clinical challenges, contributing significantly to cancer-related inflammation and mortality. Emerging evidence suggests that RT may inadvertently promote metastasis through inflammation-related immune modulations, such as the dysregulation of signaling cascades, such as focal adhesion kinase (FAK), phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT), p38 mitogen-activated protein kinase (p38 MAPK), and nuclear factor-kappa B (NF-κB) signaling cascades. Targeting these pro-metastatic pathways using specific inflammatory inhibitors and clinically available repurposed drugs has shown promise in 2 This is a provisional file, not the final typeset article numerous preclinical models, offering a rational approach to mitigate radiation-induced inflammation in metastatic progression. With the rapid advancements of high-throughput sequencing and medical imaging technologies, radiogenomics, which incorporates medical imaging and genomic data, offers great promise for cancer diagnosis, tumor classification, treatment selection, and disease monitoring through the identification of predictive and prognostic biomarkers. This review critically unravels the immune modulation underlying radiation-induced inflammation in cancer metastasis and highlights the need for comprehensive studies combining radiogenomics with RT and targeted therapies. Such approaches hold potential to improve therapeutic outcomes and reduce metastatic burden, paving the way for more effective and personalized cancer treatments.