Open Access

REVIEW

Immune Checkpoint Inhibitors Combined with Oncolytic Virotherapy: Synergy, Heterogeneity, and Safety in Cancer Treatment

Yi Feng^1,#, Haoxin Yang², Guicai Liang¹, Jun Chen³, Tao Li¹, Yingjuan Wang⁴, Jilin Chang¹, Yan Li³, Meng Yang¹, Xilong Zhou¹, Zhiqiang Wang^5,*, Chunlei Ge^1,*

1 Department of Cancer Biotherapy Center, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, 650118, China
2 Department of Laboratory Animal Science, Kunming Medical University, Kunming, 650500, China
3 Department of Neurosurgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, 650118, China
4 Department of Radiology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, 650118, China
5 Department of Radiation Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China

* Corresponding Authors: Zhiqiang Wang. Email: ; Chunlei Ge. Email:
# First author: Yi Feng

(This article belongs to the Special Issue: New Insights in Drug Resistance of Cancer Therapy: A New Wine in an Old Bottle)

Oncology Research 2025, 33(12), 3801-3836. https://doi.org/10.32604/or.2025.067824

Received 13 May 2025; Accepted 01 August 2025; Issue published 27 November 2025

Abstract

Immune checkpoint inhibitor (ICI) has limited efficacy in the treatment of immune “cold” tumors. Due to insufficient T cell infiltration and heterogeneous programmed death ligand 1 (PD-L1) expression, the ORR is only 5%–8% compared with 30%–40% of “hot” tumors. This article reviews the synergistic mechanism, clinical efficacy and optimization strategy of oncolytic virus (OVs) combined with ICIs in the treatment of refractory malignant tumors. Systematic analysis of mechanistic interactions across tumor types and clinical trial data demonstrates that OVs transform the immunosuppressive microenvironment by inducing immunogenic cell death and activating innate immunity. Concurrently, ICIs enhance adaptive immunity by reversing T-cell exhaustion and expanding T-cell diversity. Clinical trials in melanoma, head and neck cancer and breast cancer showed superior efficacy. The Objective Response Rate (ORR) of combination therapy was 39%–62%, while the ORR of ICI monotherapy was 18%. Treatment heterogeneity is mainly attributed to virus-related factors, including targeting specificity and replication efficiency, tumor characteristics, such as antigen presenting ability and mutation load, and host immune status, including pre-existing antiviral antibodies and microbiome composition. This combined approach represents a paradigm shift in cancer immunotherapy, which effectively transforms immune “cold” tumors into “hot” tumors through the continuous activation of innate and adaptive immune responses. In the future, it is expected to improve the therapeutic effect of treatment-resistant malignant tumors through the integration of immune regulatory molecules, accurate biomarkers to guide the treatment scheme and triple combination strategy by a new generation of engineering viruses.

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