Non-small cell lung cancers (NSCLCs) oncolysis using coxsackievirus B5 and synergistic DNA-damage response inhibitors

Sep 24, 2026

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Studies on oncolytic viruses increasingly emphasize mechanisms linking viral infection to host stress responses and tumor cell death. This work screened coxsackievirus B5/Faulkner for oncolytic activity against non-small cell lung cancers by driving apoptosis and autophagy. For refractory NSCLCs, DNA-PK or ATM inhibitors synergized with CV-B5/F to intensify double-strand DNA breaks and further promote apoptosis and autophagy. Mechanistically, PERK activation and ER stress–induced exacerbated death contributed, while STING degradation via ERphagy enhanced viral replication. No treatment-related deaths were observed, supporting CV-B5/F combined therapy as a potential NSCLC approach.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

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Introduction

Oncolytic viruses and therapeutic rationale

Enteroviruses as oncolytic candidates and limitations

Targeting mechanisms and need for defined receptor/effector pathways

Signal Transduction [and Targeted Therapy](and Targeted Therapy www.nature.com/sigtrans)[ www.nature.com/sigtrans](and Targeted Therapy www.nature.com/sigtrans) Non-small cell lung cancers (NSCLCs) oncolysis using coxsackievirus B5 and synergistic DNA-damage response inhibitors Bopei Cui1,2, Lifang Song 1,2, Qian Wang1, Kelei Li1,3, Qian He1, Xing Wu1, Fan Gao 1, Mingchen Liu1, Chaoqiang An1,3, Qiushuang Gao 1, Chaoying Hu1, Xiaotian Hao 1, Fangyu Dong 1,4, Jiuyue Zhou4, Dong Liu 1,5, Ziyang Song 1,6, Xujia Yan1,5, Jialu Zhang 1, Yu Bai1, Qunying Mao1 ✉, Xiaoming Yang 2,7 ✉ and Zhenglun Liang 1 ✉ | | | | | --- | --- | --- | | | With the continuous in-depth study of the interaction mechanism between viruses and hosts, the virus has become a promising tool in cancer treatment. In fact, many oncolytic viruses with selectivity and effectiveness have been used in cancer therapy. Human enterovirus is one of the most convenient sources to generate oncolytic viruses, however, the high seroprevalence of some enteroviruses limits its application which urges to exploit more oncolytic enteroviruses. In this study, coxsackievirus B5/ Faulkner (CV-B5/F) was screened for its potential oncolytic effect against non-small cell lung cancers (NSCLCs) through inducing apoptosis and autophagy. For refractory NSCLCs, DNA-dependent protein kinase (DNA-PK) or ataxia telangiectasia mutated protein (ATM) inhibitors can synergize with CV-B5/F to promote refractory cell death. Here, we showed that viral infection triggered endoplasmic reticulum (ER) stress-related pro-apoptosis and autophagy signals, whereas repair for double-stranded DNA breaks (DSBs) contributed to cell survival which can be antagonized by inhibitor-induced cell death, manifesting exacerbated DSBs, apoptosis, and autophagy. Mechanistically, PERK pathway was activated by the combination of CV-B5/F and inhibitor, and the irreversible ER stress-induced exacerbated cell death. Furthermore, the degradation of activated STING by ERphagy promoted viral replication. Meanwhile, no treatment-related deaths due to CV-B5/F and/or inhibitors occurred. Conclusively, our study identiﬁes an oncolytic CV-B5/F and the synergistic effects of inhibitors of DNA-PK or ATM, which is a | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | potential therapy for NSCLCs. | | | | Signal Transduction and Targeted Therapy (2023)8:366 ; [https://doi.org/10.1038/s41392-023-01603-4](https://doi.org/10.1038/s41392-023-01603-4) | | | | | | INTRODUCTION The disability-adjusted life years of tumors were approximately 105 million years globally in 2019 .1 Currently, immunotherapy is a hot spot for tumor treatment because of its targeting and security, including chimeric antigen receptor T-cell immunotherapy, immune checkpoint blockade, and oncolytic virus (OV) .2 OVs are natural or genetically-modiﬁed viruses that can only recognize and lyse tumor cells, but cannot mire normal cells.3 For instance, T-vec was constructed to treat melanoma and was approved by the FDA in 2015 .4 Moreover, many types of OVs, including DNA and RNA viruses, are in the research stage.5 The targeting and potency of an OV depend on many aspects. On the one hand, it relies on the expression of speciﬁc receptors on tumors but not on normal cells. However, signaling pathways can assist or compromise this effect. Furthermore, neutralizing antibody levels at baseline or primed by OV causes concerns of a limited “one shot” approach.6,7 Therefore, OV is required to be lowseroprevalent and its deﬁnite receptor and oncolytic mechanism should be determined. Recently, oncolytic enteroviruses have been reported to exert anoncolytic effect on tumor cells in a receptor-dependent manner, including coxsackievirus A21 (CV-A21), Coxsackievirus B3 (CV-B3), and Echovirus 7.8–11 For CV-A21, melanoma is the most sensitive cell type which is highly pr

FAQs

What is the main goal of this study on CV-B5/F?

To evaluate whether coxsackievirus B5/Faulkner can exert oncolytic effects against non-small cell lung cancers by inducing apoptosis and autophagy.

How do DNA-PK or ATM inhibitors enhance treatment of refractory NSCLCs?

They synergize with CV-B5/F to promote refractory cell death by exacerbating double-strand DNA breaks and strengthening apoptosis and autophagy.

What mechanism links ER stress and viral replication in the study?

Viral infection triggers ER stress-related pro-apoptosis and autophagy signals; PERK pathway activation contributes to exacerbated death, and degradation of activated STING by ERphagy promotes viral replication.

Sep 24, 2026

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