Bacteriophage-Based Platforms in Translational Oncology: Nanomedicines for Precision Targeting and Immune Reprogramming

Despite substantial advances in cancer therapy, clinical outcomes remain limited by intratumoral heterogeneity, therapeutic resistance, impaired drug penetration, and an immunosuppressive tumor microenvironment. This narrative review examines bacteriophages and phage-derived particles as programmable nanobiological platforms for precision oncology, integrating molecular targeting, immune modulation, therapeutic delivery, microbiome engineering, and physical tumor therapy within a multiscale systems-oncology framework. Distinct phage architecture provides complementary therapeutic functions. Filamentous phages such as M13 and fd offer high-density pIII/pVIII display for tumor-homing ligands, imaging probes, and therapeutic cargos, whereas T4 provides capsid-associated motifs, including KGD within gp24, that can interact with tumor-associated integrins. RGD4C-engineered M13-derived and AAVP platforms target αvβ3/αvβ5 integrins and have enabled tumor-directed delivery of therapeutic transgenes, including HSV-tk, sTNF-α, and TRAIL; incorporation of the fusogenic peptide H5WYG into pVIII can further facilitate endosomal escape. Phage-associated nucleic acids can provide intrinsic immunostimulatory activity: DNA-containing phages such as T7 and λ can engage TLR9/MyD88 signaling in relevant experimental contexts, thereby promoting antigen-presenting cell activation and macrophage reprogramming toward an antitumoral M1-like phenotype. Phage display also supports antigen cross-presentation, while genome-free Qβ and MS2 virus-like particles provide highly repetitive scaffolds for tumor-associated antigen and glycopeptide vaccination. Beyond direct tumor targeting, engineered or lytic phages directed against Fusobacterium nucleatum, including M13-based M13@Ag and phage ØTCUFN3, illustrate the potential of microbiome-directed interventions to remodel tumor–microbial–immune interactions. Physical therapeutic platforms, including M13@Pd/NLG, T7-AuNP, and T4-Ce6/catalase, further extend phage functionality to photothermal and photodynamic strategies. However, translation remains constrained by biodistribution, clearance by the mononuclear phagocyte system, anti-phage immunity, endotoxin control, manufacturing reproducibility, and limited clinical validation. Collectively, these studies support the use of bacteriophages as multifunctional and reconfigurable biological scaffolds capable of integrating targeting, immune activation, therapeutic delivery, microbiome modulation, and physical intervention across interconnected biological scales. Their principal translational value is unlikely to derive from universal superiority over conventional nanomedicines, but rather from rationally engineered combinations tailored to specific tumor and immune phenotypes. Establishing reproducible manufacturing, pharmacokinetic and pharmacodynamic relationships, biomarker-guided patient selection, and rigorous clinical efficacy and safety profiles will be essential for defining the role of phage-based platforms in precision oncology.