Oncolytic Viruses as In Situ Cancer Vaccines: Tumor Microenvironment Remodeling, Checkpoint Inhibitor Synergy, and Biomarker-Guided Clinical Translation

Oncolytic viruses (OVs) are increasingly viewed not only as tumor-lysing agents but also as immunotherapeutic platforms capable of functioning as in situ cancer vaccines. By selectively infecting malignant cells, inducing immunogenic cell death, releasing tumor-associated antigens and danger signals, and activating innate and adaptive immunity, OVs can remodel immune-desert or immune-excluded tumors. This narrative review integrates mechanistic and clinical evidence on tumor-selective viral replication, antigen presentation, dendritic-cell activation, type I interferon signaling, and the recruitment of cytotoxic T lymphocytes and natural killer cells. Particular attention is given to the effects of OVs on regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, cancer-associated fibroblasts, and extracellular matrix barriers. We further examine the biological rationale and clinical outcomes of combining OVs with immune checkpoint inhibitors, emphasizing the discrepancy between promising preclinical findings and inconsistent clinical efficacy. A stepwise translational framework is proposed to distinguish failures in delivery and replication from inadequate immune conversion, checkpoint-restrained immunity, and non-checkpoint-dominant resistance. Finally, we discuss antiviral immunity, safety, viral engineering, and tissue-based, circulating, and genomic biomarkers that may support patient selection and guide next-generation OV-based combination strategies.