Interferon alpha-2b (IFNα2b) in precision oncology: Innovations in delivery and combinatorial immunotherapy

Interferon alpha-2b (IFNα2b) has been a pivotal drug in cancer immunotherapy since its FDA approval in the 1980s, demonstrating both direct and indirect anticancer benefits. It directly triggers cell cycle arrest and death via Bax/Bcl-2 regulation and inhibits angiogenesis, primarily mediated by the JAK-STAT system, which activates over 300 interferon-stimulated genes (ISGs). IFNα2b indirectly increases immune surveillance by augmenting natural killer (NK) cell cytotoxicity, facilitating dendritic cell (DC) maturation, and bolstering T-cell activation, while concurrently inhibiting regulatory T cells (Tregs) and immunosuppressive cytokines such as TGF-β. Clinically, IFNα2b has shown effectiveness in melanoma, renal cell carcinoma (RCC), and hematologic malignancies. In stage III melanoma, high-dose IFNα2b enhances relapse-free survival, decreasing recurrence by 28 %. RCC exhibits a response to IFNα2b in conjunction with interleukin-2, attaining an 18 % objective response rate, but chronic myelogenous leukemia (CML) demonstrates a 76 % survival rate at 36 months. Combination therapy, particularly those incorporating immune checkpoint inhibitors such as pembrolizumab, have enhanced results in advanced melanoma, with objective response rates of 60 %. Innovations like pegylation (prolonging half-life to 48–72 h) and Probody technology (Pb-IFNα2b) enhance safety and tumor specificity. Nonetheless, obstacles persist, including as dose-limiting toxicities, resistance associated with JAK-STAT dysregulation, and immunosuppressive tumor microenvironments. Innovative approaches like as dendritic cell-based vaccinations, biomarker-driven patient stratification, and sophisticated delivery methods seek to surmount these obstacles. As precision oncology advances, IFNα2b continues to be an essential therapeutic agent, connecting its historical significance with future-oriented immunotherapy.