The understanding of immune biology and the development of newer generations of immunotherapies have opened a new stage to combat many diseases, including cancer. Among these, oncolytic viruses represent a unique class of virus-based immunotherapy that infect and lyse tumor cells while stimulating systemic anti-tumor immune responses. However, the field of oncolytic virotherapy has cycled through peaks of enthusiasm and deep troughs. Following T-VEC’s approval in 2015, enthusiasm propelled research across many viral platforms. Nevertheless, this substantial investment has often failed to yield expected clinical benefits: numerous clinical trials have ended in partial or complete failure.

One contributing factor is the pursuit of a panacea; a single viral platform presumed to be broadly effective across patients and cancer types. This approach often preceded rigorous interrogation of mechanisms of action and resistance. The immune response is dynamic and varies across patients, influenced by genetic and non-genetic factors that must be thoroughly studied to improve ongoing strategies and develop new ones.

This Research Topic aims to redirect focus toward mechanistic understanding of existing virotherapies and the rational design of novel candidates. We particularly welcome submissions that center on the biology of resistance, rigorous mechanistic studies, and translational strategies that use that knowledge to guide the design of more effective and predictable oncolytic virotherapy. We also encourage publication of negative results, clinical failures and “lessons learned” to inform future design and trial strategy.

We invite authors to submit original research articles, reviews, and systematic reviews that contribute to the fields of immune therapeutics resistance and advancing oncolytic virotherapy. Particularly, we welcome submissions related to, but not limited to, the following sub-themes:

• Illuminate molecular, cellular and immunological mechanisms underlying oncolytic virus activity and failure.
• Determinants of primary and acquired resistance (genetic, epigenetic, microenvironmental, immune-mediated).
• Advance rational criteria for vector selection, genetic modification and rationale-driven payload design grounded in testable hypotheses.
• Engineering strategies to improve specificity, safety, delivery and persistence.
• Predictive preclinical models (advanced in vitro systems, organoids, immunocompetent and humanized in vivo models).
• Mechanistically justified combination therapies (immune checkpoint inhibitors, targeted agents, chemotherapy, radiotherapy) and associated translational data.
• Highlight translational strategies that convert mechanistic insights into clinically actionable improvements (biomarkers, patient selection, combination strategies).
• Biomarkers for response, resistance and patient stratification.
• Systematic analyses of clinical and preclinical failures: case studies, meta-analyses and “lessons learned".
• Emerging platforms and delivery systems (retargeted viruses, RNA-based approaches, non-viral delivery innovations).

Topic Editors, Dr. Emanuele Sasso and Dr. Darshak Bhatt, declare no competing interests with regard to the Research Topic subject.

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Dissecting Molecular Mechanisms of Action and Resistance in Oncolytic Virotherapy