Zhifeng Qu,1 Linlin Shi,2 Pei Wang,1 Anshun Zhao,2 Xuewei Zheng,3 Qinan Yin1,3 

1Department of Radiation Oncology; Cancer Institute, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, People’s Republic of China; 2Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment; Henan Key Laboratory of Cancer Epigenetics; College of Basic Medicine and Forensic Medicine, Cancer Hospital, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, People’s Republic of China; 3Precision Medicine Laboratory, School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, People’s Republic of China

Correspondence: Qinan Yin, Department of Radiation Oncology; Cancer Institute, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, No. 636, Guanlin Avenue, Luoyang, 471003, People’s Republic of China, Email qinanyin@haust.edu.cn Xuewei Zheng Precision Medicine Laboratory, School of Medical Technology and Engineering, Henan University of Science and Technology, No. 263, Kaiyuan Avenue, Luoyang, 471000, People’s Republic of China, Email xwzheng0529@163.com

Abstract: Esophageal squamous cell carcinoma (ESCC) is characterized by chronic inflammation, immune evasion, and resistance to RT. Inflammatory pathways such as nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3), and cyclooxygenase 2 (COX-2) promote tumor progression and reduce radiosensitivity. RT activates pro-inflammatory cytokines and upregulates immune checkpoints including programmed death 1 (PD-1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), which contribute to immune suppression and treatment failure. Dual targeting of inflammatory and immune checkpoint pathways has shown potential to reverse radio resistance and enhance therapeutic response. Inhibition of COX-2 can reduce inflammation and improve tumor control, while blockade of PD-1 can restore T cell function and promote antitumor immunity. Strategies that integrate anti-inflammatory components, immune checkpoint inhibitors (ICIs), and RT guided by molecular profiling may improve treatment outcomes in ESCC. This review focuses on the biological basis of inflammation-mediated radio resistance and presents dual targeting approaches as promising options to overcome current therapeutic limitations.

Keywords: esophageal squamous cell carcinoma, inflammation, radiotherapy (RT) resistance