Michał Iwaszko

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.

Perineural invasion (PNI) is a distinct route of cancer spread associated with neuropathic pain, local recurrence, and poor survival across many solid tumours. Increasing evidence shows that PNI is not only a structural pattern of invasion but also a dynamic biological process involving neurodegeneration, nociceptor sensitisation, and marked local immunosuppression. This narrative review synthesises experimental, translational, and clinical data on the molecular, neurological, and immunological mechanisms of PNI in solid malignancies. PNI arises through complex crosstalk between tumour cells, Schwann cells, macrophages, fibroblasts, and neurotrophic pathways, leading to peripheral nerve remodelling, axonal degeneration, and abnormal regeneration. These changes promote neuropathic pain through ion-channel dysregulation, neurotrophin-driven sensitisation, and pathological neuroplasticity. At the same time, PNI creates an immunosuppressive microenvironment enriched in Tregs, M2 macrophages, and myeloid-derived suppressor cells, shaped by cholinergic, adrenergic, and neuropeptidergic signalling, which may contribute to immune exclusion and resistance to immunotherapy. We propose that PNI should be understood as a neuro-immuno-metabolic process and that recognising the PNI–pain–immunosuppression triad may support the development of targeted neuroprotective, analgesic, and immunomodulatory therapies.