Cancer gene therapy: historical perspectives, current applications, and future directions

Gene therapy has emerged as a transformative approach in cancer treatment, leveraging genetic modifications to target malignancies with enhanced precision. Early efforts faced challenges such as inefficient vector delivery (< 5% tumor transduction rates with first-generation adenoviruses), immune responses (neutralizing antibodies in ~ 30% of patients), and limited clinical efficacy (< 10% objective response rates in 1990s trials). However, advancements in viral and non-viral vectors (e.g., AAVs achieving > 50% transduction efficiency in solid tumors), alongside CRISPR-Cas9 (90% target gene knockout rates in preclinical models) and RNA interference technologies, have revolutionized the field. Presently, gene therapy strategies, including tumor suppressor gene restoration, oncogene silencing, and immune modulation, demonstrate promising clinical outcomes. Despite persistent hurdles like off-target effects and high costs, emerging innovations in personalized gene editing, oncolytic viruses, and combination therapies signal a paradigm shift in oncology. This review explores the evolution of gene therapy for cancer, highlighting key milestones, current applications, and future directions that could unlock its full therapeutic potential.