This study is led by Prof. Jun Wang (School of Biomedical Sciences and Engineering, South China University of Technology), Prof. Cong-Fei Xu (School of Biomedical Sciences and Engineering, South China University of Technology), and Prof. Zi-Dong Lu (School of Medicine, South China University of Technology).
Therapeutic cancer vaccines are severely limited by tumor clonal heterogeneity and antigenic plasticity, making it incredibly difficult to identify an effective, uniformly expressed target antigen. Bacterial superantigens (SAgs) offer a powerful alternative by directly bridging major histocompatibility complex class Ⅱ (MHC-Π) molecules on antigen-presenting cells with T-cell receptors (TCRs). This interaction bypasses standard intracellular processing to trigger a robust, broad activation of T cells. However, systemic administration of recombinant SAg proteins carries a prohibitive risk of lethal cytokine storms and severe organ toxicity.
To safely harness this immense potency, Wang et al. developed iCLAN TSP-SAg , a platform that encapsulates tumor-specific promoter-driven SAg expression plasmids inside ionizable/cationic lipid-assisted polymeric nanoparticles (iCLAN). Following systemic administration, this nano-activator established a strict transcriptional gate. While the physical nanocarrier distributed to clearance organs, SAg production and secretion were exclusively executed within tumor cells, effectively sparing normal tissues.
In animal studies, the nano-activator demonstrated an exceptional biosafety profile. Unlike recombinant SAg protein therapies that caused widespread systemic inflammation, mice treated with iCLAN TSP-SAg maintained normal serum cytokine levels and healthy liver and kidney biomarkers. Furthermore, the platform successfully remodeled the immunosuppressive tumor microenvironment by recruiting dendritic cells while significantly reducing regulatory T cells and myeloid-derived suppressor cells. When combined with anti-PD-1 antibodies, the nano-activator eradicated established solid tumors in two-thirds of the treated mice and induced a durable, systemic immune memory that conferred complete protection against secondary tumor challenges.
In summary, this study introduces a compelling off-the-shelf vaccination modality that replaces conventional antigen nomination with tumor-confined, transcriptionally gated SAg production. This antigen-independent cancer vaccination strategy addresses key limitations of current cancer vaccines by enabling broad and safe activation of tumor-infiltrating T cells.
Science Bulletin