Staphylococcal enterotoxins in cancer immunotherapy: An overview of translational advances and targeting strategies.

Staphylococcal enterotoxins (SEs) are superantigens that polyclonally activate T cells by cross-linking MHC class II on antigen-presenting cells with T cell receptor (TCR) Vβ regions, generating potent IL-2/IFN-γ/TNF responses distinct from conventional peptide-MHC-restricted activation. This review synthesizes mechanistic and translational evidence for SEs in oncology, emphasizing disease-relevant contexts and advanced engineering strategies that improve therapeutic index. Preclinical studies demonstrate antitumor activity across melanoma, glioblastoma, renal cell carcinoma, bladder cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, squamous cell carcinoma, and hematologic malignancies (e.g., acute myeloid leukemia, lymphoma). Tumor-targeted superantigen platforms, such as antibody or ligand-SE fusion proteins and oncolytic vectors encoding Ses, concentrate activity intratumorally, increase intratumoral IFN-γ/TNF, reduce proliferation and angiogenesis, and enhance necrosis while limiting systemic exposure. Engineered SE variants (for example, SEB with attenuated pyrogenicity) and localized delivery further mitigate risks associated with cytokine release. Early clinical experiences with SE-based constructs and SE-modified tumor vaccines report feasibility and signals of activity in head and neck cancer, glioma, renal cell carcinoma, and myeloma, but small, heterogeneous studies limit definitive conclusions. Although SEs can trigger cytokine storm and off-target activation via MHC II on healthy tissues, risk can be reduced through intratumoral/regional dosing, tumor-targeted fusions, dose-schedule optimization, and indication selection informed by MHC II biology; paradoxical, disease-specific effects (e.g., in cutaneous T-cell lymphoma) highlight the importance of microbiome-aware protocols. Priorities for translation include disease-focused development in MHC II-II-permissive tumors, combinations with immune checkpoint inhibitors, and biomarker-anchored trials integrating multi-omics and patient selection. With targeted engineering and controlled delivery, SEs can evolve from broadly inflammatory agents into precise immuno-oncology tools with meaningful clinical impact. This review underscores that, with targeted engineering, controlled delivery, and biomarker-guided patient selection, SEs can be advanced from broadly inflammatory agents to precise immuno-oncology platforms ready for rigorous clinical evaluation.