Luyi Ye,1,2,* Meng Gao,3,* Yue Chen,3 Yuting Zhu,2 Jilong Wang,1,2 Zhangquan Wang1 

1Department of Clinical Medical Laboratory Center, Tiantai People’s Hospital of Zhejiang Province (Tiantai Branch of Zhejiang Provincial People’s Hospital), Hangzhou Medical College, Taizhou, Zhejiang, 317200, People’s Republic of China; 2Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325000, People’s Republic of China; 3Department of Gastroenterology, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, 230011, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jilong Wang, Email wangjilong@ucas.ac.cn Zhangquan Wang, Email 15867093721@163.com

Abstract: Oncolytic virus (OVs) therapy has emerged as a promising modality in cancer immunotherapy, attracting growing attention for its multifaceted mechanisms of tumor elimination. However, its efficacy as a monotherapy remains constrained by physiological barriers, limited delivery routes, and suboptimal immune activation. Phototherapy, an innovative and rapidly advancing cancer treatment technology, can mitigate these limitations when used in conjunction with OVs, enhancing viral delivery, amplifying tumor destruction, and boosting antitumor immune responses. This review provides the first comprehensive analysis of synergistic integration of OVs with both photodynamic therapy (PDT) and photothermal therapy (PTT). It also explores their applications in optical imaging-guided diagnosis and optogenetically controlled delivery. Furthermore, it discusses emerging strategies involving biomimetic virus or viroid-based vectors in conjunction with phototherapy, and delves into the immunomodulatory mechanisms of this combinatorial approach. While promising in preclinical models, these combined strategies are still largely in early-stage research. Challenges such as limited light penetration, delivery efficiency, and safety concerns remain to be addressed for clinical translation. Consequently, the integration of OV therapy and phototherapy represents a compelling strategy in cancer treatment, offering significant promise for advancing precision oncology and next-generation immunotherapies.

Keywords: phototherapy, oncolytic virus, immunotherapy, optogenetics