Superantigens in Cancer Immunotherapy: Mechanisms, Engineering Strategies, and Therapeutic Potential
ABSTRACT Cancer immunotherapy has reshaped modern oncology by enabling the immune system to recognize and eliminate malignant cells. However, many solid tumors still respond poorly because of weak T‐cell activation and an immunosuppressive tumor microenvironment. Bacterial superantigens (SAgs) represent a unique class of immunomodulatory proteins capable of overcoming these limitations through direct activation of large T‐cell populations. Unlike conventional antigens, superantigens bypass classical antigen processing by simultaneously binding major histocompatibility complex class II molecules and T‐cell receptor Vβ domains, triggering rapid cytokine release and extensive immune activation. Although this potent mechanism has historically been associated with severe systemic toxicity, recent advances in protein engineering and targeted delivery have renewed interest in their therapeutic potential. This review discusses the structural and immunological basis of superantigen activity and highlights emerging strategies designed to improve tumor specificity and safety, including engineered low‐toxicity variants, antibody‐superantigen fusion proteins, nanoparticle‐based delivery systems, and tumor‐targeted constructs. We further examine how superantigens reshape the tumor microenvironment and synergize with immune checkpoint blockade, adoptive cell therapies, and other T‐cell‐redirecting approaches. Together, these advances position engineered superantigens as promising immune‐amplifying platforms with the potential to complement existing cancer immunotherapies and improve responses in poorly immunogenic tumors.