Oncolytic Virotherapy and Immunogenic Cell Death: Mechanisms, Platforms, and Clinical Translation

Sep 22, 2026

Uploaded by Sarah

Oncolytic viruses provide a paradigm-shifting approach to cancer immunotherapy by acting as in situ vaccines that convert immunologically “cold” tumors into “hot” tumors via immunogenic cell death (ICD). The review explains how virus-induced ICD is driven by calreticulin exposure, ATP secretion, HMGB1 release, and type I interferon production. It compares DNA and RNA virus platforms, and summarizes clinical trial evidence showing synergy with checkpoint inhibitors. RNA viruses induce stronger type I interferon and show superior outcomes, including CAPRA results for Coxsackievirus A21, selectivity of Coxsackievirus A11, and microRNA-targeted safety attenuation for Coxsackievirus B3.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages37

Reading Time1 h 33 min

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Introduction: The Challenge of Immunologically Cold Tumors

Checkpoint Inhibitors and the Cold Tumor Problem

Oncolytic Viruses as In Situ Cancer Vaccines

Review Oncolytic Virotherapy and Immunogenic Cell Death: Mechanisms, Platforms, and Clinical Translation Hiroyuki Inoue Academic Editors: Arianna Calistriand Sandra Tuyaerts Received: 17 February 2026 Revised: 19 March 2026 Accepted: 27 March 2026 Published: 13 April 2026 Copyright: © 2026 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. Department of Respiratory Medicine, Fukuoka University Hospital, Fukuoka 814-0180, Japan; [hinoue@fukuoka-u.ac.jp](hinoue@fukuoka-u.ac.jp); Tel.: +81-092-811-1011 Abstract Oncolytic viruses represent a paradigm-shifting approach to cancer immunotherapy, functioning as in situ vaccines that convert immunologically “cold” tumors into “hot” tumors through induction of immunogenic cell death (ICD) . Despite the clinical success of checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), many patients exhibit primary or acquired resistance due to insufficient tumor immunogenicity and exclusion of tumor-infiltrating lymphocytes. Oncolytic viruses address this limitation by selectively replicating in tumor cells, inducing robust ICD characterized by four cardinal hallmarks: calreticulin exposure, ATP secretion, HMGB1 release, and type I interferon production. This review systematically examines the molecular mechanisms underlying virus-induced ICD, compares DNA virus platforms (Vaccinia, HSV-1, Adenovirus) with RNA virus platforms (Coxsackieviruses A21, A11, and B3), and analyzes clinical trial data demonstrating synergistic efficacy when combined with checkpoint inhibitors. Notably, RNA viruses generate higher type I interferon responses compared to DNA viruses, correlating with superior clinical outcomes. Coxsackievirus A21 combined with pembrolizumab achieved a 47% objective response rate in melanoma in the CAPRA trial, representing notable efficacy exceeding either monotherapy. Coxsackievirus A11 demonstrates exceptional selectivity for thoracic cancers through ICAM-1-dependent receptor tropism and potent immunogenic cell death induction. Japanese researchers have pioneered microRNAtargeted Coxsackievirus B3, achieving cardiac safety attenuation while preserving complete oncolytic potency and ICD-inducing capacity. This comprehensive analysis synthesizes molecular mechanisms, platform comparisons, clinical efficacy data, and translational challenges to guide future development of oncolytic virotherapy as a cornerstone of cancer immunotherapy. Keywords: oncolytic virus; immunogenic cell death; checkpoint inhibitor; coxsackievirus; coxsackievirus A11; type I interferon; tumor microenvironment; cancer immunotherapy 1. Introduction: The Challenge of Immunologically Cold Tumors 1.1. Checkpoint Inhibitors and the Cold Tumor Problem The advent of immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 has revolutionized cancer therapy, demonstrating durable responses and long-term survival benefits across multiple cancer types [1,2] . Ipilimumab, the first FDA-approved CTLA-4 inhibitor, improved overall survival in metastatic melanoma patients, establishing immunotherapy as a viable treatment modality [3] . Subsequently, PD-1/PD-L1 inhibitors have achieved approval for melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, and numerous other malignancies, with some patients achieving complete responses lasting years beyond treatment cessation [1,2] . However, the majority of cancer patients fail to respond to checkpoint inhibitor monotherapy. Response rates typically range from 15–45% depending on tumor type, with primary resistance occurring in 40–65% of patients and acquired resistance developing in 25–40% of initial responders [4,5] . The fundamental limitation is that checkpoint inhibitors require pre-ex

FAQs

What problem do oncolytic viruses aim to solve in cancer immunotherapy?

The review reports synergistic clinical efficacy when oncolytic viruses are combined with checkpoint inhibitors, with examples including CAPRA trial results for Coxsackievirus A21 plus pembrolizumab.

Sep 22, 2026

Uploaded by Sarah