# Oncolytic Viruses in Cancer Immunotherapy: From Molecular Engineering to Clinical Translation

## TL;DR

Oncolytic viruses fight cancer by destroying tumors and boosting the immune system, with new engineering techniques improving their effectiveness and safety.

## Contribution

Advanced viral engineering strategies and combination therapies are shown to enhance tumor selectivity and therapeutic efficacy of oncolytic viruses.

## Key findings

- Oncolytic viruses induce antitumor immunity through direct tumor lysis and immunogenic cell death.
- Next-generation oncolytic viruses armed with immunostimulatory payloads improve localized immune modulation.
- Combination therapies with oncolytic viruses and other treatments help overcome tumor resistance and antiviral immunity.

## Abstract

What are the main findings?
Oncolytic viruses exert antitumor activity through direct tumor lysis and induction of systemic antitumor immunity.Advanced viral engineering strategies enhance tumor selectivity, immune activation, and therapeutic efficacy.

Oncolytic viruses exert antitumor activity through direct tumor lysis and induction of systemic antitumor immunity.

Advanced viral engineering strategies enhance tumor selectivity, immune activation, and therapeutic efficacy.

What are the implications of the main findings?
Rational combination therapies are critical to overcome antiviral immunity and tumor resistance.The findings guide the development of next-generation oncolytic virus platforms and clinical trial design.

Rational combination therapies are critical to overcome antiviral immunity and tumor resistance.

The findings guide the development of next-generation oncolytic virus platforms and clinical trial design.

Cancer immunotherapy has transformed modern oncology, yet durable responses remain limited for many patients due to immune exclusion, adaptive resistance, and tumor heterogeneity. Oncolytic viruses (OVs) have emerged as a novel class of immunotherapeutics that unify direct tumor cytolysis with stimulation of antitumor immunity. By inducing immunogenic cell death (ICD) and releasing tumor-associated antigens (TAAs), OVs remodel the tumor microenvironment (TME) into an inflamed and immune-permissive niche capable of enabling systemic immune activation. Rapid advances in viral engineering have strengthened the translational potential of OVs through tumor-selective gene deletions, tumor-specific promoters, microRNA-based detargeting, and receptor-retargeting strategies that collectively enhance safety, specificity, and intratumoral propagation. Next-generation OVs are increasingly “armed” with immunostimulatory payloads—including cytokines, chemokines, checkpoint inhibitors, bispecific T-cell engagers, and suicide gene systems—allowing localized immune modulation with reduced systemic toxicity. These innovations have propelled significant clinical progress, exemplified by the approvals of talimogene laherparepvec (T-VEC), G47Δ, and H101, and have driven a surge of combination trials integrating OVs with immune checkpoint blockade, adoptive cell therapies, radiotherapy, and targeted therapies to overcome multilayered tumor immune resistance. Despite this momentum, clinical implementation remains challenged by antiviral immunity, heterogeneous viral distribution, stromal barriers, and dynamic interferon (IFN) signaling in the TME. Emerging delivery approaches, including carrier cell systems, nanotechnology-enabled viral shielding, and synthetic virology platforms, offer promising solutions to these limitations. Oncolytic virotherapy is rapidly evolving into a multifunctional immunotherapeutic platform capable of reshaping antitumor responses at both local and systemic levels. By integrating advanced viral engineering with rational combination strategies and innovative delivery technologies, OVs hold substantial potential to overcome current barriers in cancer immunotherapy and advance precision oncology. Continued translational research will be essential to fully harness their therapeutic impact and broaden their clinical applicability.