Rui Han,1,2 Xiwu Rao,3 Huiling Zhou,4 Lingeng Lu5– 7 

1Department of Chinese Medicine Oncology, The First Affiliated Hospital of Naval Medical University, Shanghai, People’s Republic of China; 2Department of Chinese Medicine, Naval Medical University, Shanghai, People’s Republic of China; 3Department of Oncology, The First Hospital Affiliated to Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 4Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, People’s Republic of China; 5Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, USA; 6School of Medicine, Center for Biomedical Data Science, Yale University, New Haven, CT, USA; 7Yale Cancer Center, Yale University, New Haven, CT, USA

Correspondence: Rui Han, Department of Chinese Medicine Oncology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People’s Republic of China, Email dianxiqiao@foxmail.com

Abstract: The utilization of PD-1/PD-L1 inhibitors marks a significant advancement in cancer therapy. However, the efficacy of monotherapy is still disappointing in a substantial subset of patients, necessitating the exploration of combinational strategies. Emerging from the promising results of the KEYNOTE-942 trial, RNA-based therapies, particularly circRNAs and piRNAs, have distinguished themselves as innovative sensitizers to immune checkpoint inhibitors (ICIs). These non-coding RNAs, notable for their stability and specificity, were once underrecognized but are now known for their crucial roles in regulating PD-L1 expression and bolstering anti-cancer immunity. Our manuscript offers a comprehensive analysis of selected circRNAs and piRNAs, elucidating their immunomodulatory effects and mechanisms, thus underscoring their potential as ICIs enhancers. In conjunction with the recent Nobel Prize-awarded advancements in mRNA vaccine technology, our review highlights the transformative implications of these findings for cancer treatment. We also discuss the prospects of circRNAs and piRNAs in future therapeutic applications and research. This study pioneers the synergistic application of circRNAs and piRNAs as novel sensitizers to augment PD-1/PD-L1 inhibition therapy, demonstrating their unique roles in regulating PD-L1 expression and modulating immune responses. Our findings offer a groundbreaking approach for enhancing the efficacy of cancer immunotherapy, opening new avenues for treatment strategies. This abstract aims to encapsulate the essence of our research and the burgeoning role of these non-coding RNAs in enhancing PD-1/PD-L1 inhibition therapy, encouraging further investigation into this promising field.

Keywords: CircRNA, piwi-RNA, immunotherapy, PD-1/PD-L1 blockade, immunotherapy sensitizer, combination therapy