Abstract::Talimogene laherparepvec (T-VEC), the first FDA-approved oncolytic viral therapy, has transformed
cancer immunotherapy since its 2015 approval for unresectable melanoma. Engineered from Herpes Simplex
Virus type 1 (HSV-1) with deletions in ICP34.5 and ICP47 genes and GM-CSF insertion, T-VEC selectively
replicates within the tumor cells, inducing lysis and releasing tumor-derived antigens while stimulating systemic
antitumor immunity through dendritic cell activation. Although extensively studied for melanoma, its potential
extends beyond this malignancy, with emerging applications in breast cancer, Head and Neck Squamous Cell
Carcinoma (HNSCC), and other solid tumors. This review synthesizes T-VEC’s mechanism of action, leveraging
dysregulated Ras signalling, impaired interferon pathways in cancer cells, its clinical outcomes, and safety profile
across these indications. While prior literature emphasizes melanoma monotherapy and combinations with immune
checkpoint inhibitors, less attention has been given to its efficacy in non-melanoma cancers and synergistic
potential with chemotherapy or radiation therapy. By exploring recent trials, such as T-VEC with neoadjuvant
chemotherapy in triple-negative breast cancer and pembrolizumab in HNSCC, highlighting its versatility. Comparative
analysis with other oncolytic viruses like HF-10, oncorine (H101), and measles virus variants positions
T-VEC within the virotherapy landscape. Key challenges—systemic delivery, immune clearance, and biomarker
development for patient selection—are addressed alongside strategies to enhance immune modulation through
novel combinations. This review underscores T-VEC’s expanding role in cancer treatment, offering clinicians’
and researchers’ insights to optimize its therapeutic horizons across diverse malignancies.