Tumor-confined nano-activators for antigen-independent broad activation of tumor-infiltrating T cells.

Cancer vaccines hold strong therapeutic promise, but their development is often hindered by the need to identify effective tumor antigens-a challenge amplified by tumor heterogeneity. Here, we report a tumor-confined nano-activator (iCLANTSP-SAg) that circumvents antigen dependence by driving localized expression of bacterial superantigens (SAgs) within tumors. This platform integrates tumor-specific promoter-driven SAg plasmids with lipid-assisted polymeric nanoparticles to enable efficient cytosolic delivery and tumor-restricted SAg production. The locally expressed SAgs elicit broad, antigen-independent activation of intratumoral CD4+ and CD8+ T cells through direct crosslinking of T-cell receptors and major histocompatibility complex class II molecules. By confining SAg expression to the tumor site, iCLANTSP-SAg minimizes systemic T-cell activation and off-target toxicity. When co-administered with anti-PD-1 antibodies, iCLANTSP-SAg eliminates established tumors in two-thirds of treated mice and induces durable immune memory that confers complete protection upon rechallenge. This strategy offers a potent and clinically translatable solution to the central challenge of antigen identification in cancer vaccine development.