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.
U. Y. Virk, H. A. Malik, M. Anwer et al.· The FASEB Journal· 0 citations
Cancer immunotherapy has transformed the treatment landscape across multiple malignancies; however, durable responses remain limited to a subset of patients due to the emergence of intrinsic and acquired resistance. Increasing evidence suggests that therapeutic immune pressure itself acts as a selective force that shapes tumour evolution, driving the outgrowth of resistant clones. In this review, we synthesise current understanding of the molecular and cellular mechanisms underlying resistance to major immunotherapeutic modalities, including immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines. We discuss tumour-intrinsic alterations such as defects in antigen presentation and immune signalling pathways, alongside tumour-extrinsic factors including immunosuppressive cell populations, metabolic constraints, and microbiome-mediated modulation. We further examine how these mechanisms converge within the tumour microenvironment to limit therapeutic efficacy. Emerging strategies to overcome resistance are highlighted, including rational combination therapies, next-generation engineered cellular platforms, and precision-guided approaches enabled by multi-omics profiling and artificial intelligence. Collectively, we propose that resistance should be understood as an adaptive consequence of therapeutic immune pressure. Building upon the principles of cancer immunoediting, we discuss how precision immune engineering, the rational design of personalised immunotherapeutic strategies informed by tumour biology, immune context, and predictive biomarkers, may be used to anticipate and overcome evolutionary escape mechanisms.
M. Anwer· International Immunopharmaco...· 0 citations
