Abstract
Oncolytic viruses (OV) are an emerging form of immunotherapy that utilize naturally occurring or engineered viruses to specifically infect and lyse tumor cells. They achieve tumor treatment through direct tumor cell killing or by inducing immunogenic cell death to enhance immune responses. However, the efficacy of OV has been suboptimal in clinical trials. This review comprehensively examines mechanisms of resistance to OV through three interconnected dimensions: The characteristics of tumors and tumor cells, factors related to stromal cells and the extracellular matrix (ECM) and the host immune status. Potential solutions targeting these mechanisms are also proposed. For instance, OV typically achieve tumor selectivity through tumor‑specific receptors or specific promoters. However, due to inter‑ and intratumoral heterogeneity, the lack of such specific receptors or promoters in tumor cells can lead to off‑target effects of OV, resulting in treatment resistance. The ECM in the tumor microenvironment, such as hyaluronic acid, may also impede viral transport. Additionally, the clearance of OV by immune cells can contribute to suboptimal therapeutic outcomes of OV treatment. Consequently, investigating predictive biomarkers of OV efficacy, utilizing ECM‑degrading enzymes and combining with immune checkpoint inhibitors represents a promising strategy to augment the therapeutic effects of OV. Synthesizing current evidence, it is anticipated that future investigations will optimize the therapeutic effects of OV treatment and bring better immunotherapeutic outcomes for cancer patients.