Local T-cell engager secretion reprograms endogenous antitumor immunity and enhances CAR-T cell persistence in solid tumors

Abstract

Background Adoptive T-cell therapies can mediate potent antitumor activity, yet their efficacy against solid tumors remains limited by antigen heterogeneity, tumor escape, and insufficient induction of endogenous antitumor immunity. Whether distinct T cell-redirecting strategies differentially engage host immune responses that contribute to durable tumor control remains poorly understood. Methods Here, we compared conventional chimeric antigen receptor (CAR)-T cells, systemic T-cell engagers (TCEs), TCE-secreting (STAb)-T cells, and dual-targeting CAR–STAb-T cells in immunocompetent mouse models of high-grade glioma. CAR–STAb-T cells combined an EGFRvIII-specific CAR with local secretion of a B7-H3-targeted TCE, enabling simultaneous direct tumor targeting and recruitment of endogenous bystander T cells. Using heterogeneous tumor models, together with functional immune profiling and T-cell receptor repertoire sequencing, we investigated the mechanisms underlying durable antitumor responses. Results Local TCE secretion markedly enhanced tumor control compared with either CAR-T cells or systemic TCE administration alone. STAb-T and CAR–STAb-T therapies prevented antigen-loss escape, expanded endogenous tumor-reactive T-cell clonotypes, promoted epitope spreading, and generated durable memory responses capable of transferring protection to secondary tumor-bearing hosts. Notably, CAR–STAb-T cells uniquely combined robust endogenous immune priming with prolonged persistence of engineered T cells, resulting in superior tumor control. TCR repertoire analyses revealed preferential expansion of tumor-reactive clonotypes associated with specific antitumoral responses, linking therapeutic efficacy to diversification of host immunity. Conclusions These findings identify local engager secretion as a mechanism that converts engineered T cells from direct cytotoxic effectors into drivers of endogenous antitumor immunity. By coupling CAR-mediated persistence with TCE-driven recruitment of polyclonal host T cells, CAR–STAb-T cells overcome antigenic heterogeneity and establish durable immune surveillance, providing a framework for next-generation adoptive cell therapies in solid tumors.