Work

Reactivating exhausted tumor-infiltrating T cells by a bispecific DC-T cell engager in mice

Year: 2026

Type: article

Abstract: Tumor infiltrating T cells (TIL) are key players in the anti-tumor immune response. However, chronic exposure to tumor-derived antigens drives the differentiation into ‘exhausted’ TILs. Whether intratumoral dendritic cells (DC) can mitigate TILs exhaustion and maintain function is unclear. Here, we develop a bispecific DC-T cell engager (BiDT), consisting of an anti-TIM3-IFN fusion protein, and demonstrate that, in preclinical mouse tumor models, this engager simultaneously targets TIM3 on exhausted TILs and activates DCs via the IFNAR receptor. Mechanistically, BiDT reactivates exhausted TIM3+TILs by preventing apoptosis through increased Bcl-2 expression and enhances DC function to reactivate T cells via IL-2 signalling and co-stimulatory CD80/86-CD28 interactions within the tumor microenvironment. Finally, to mitigate IFNα-induced toxicity, we engineer a Pro-BiDT engager featuring a pro-IFNα and report potent antitumor activity with reduced systemic toxicity. Thus, by bridging DC-T cells together, BiDT treatment enhances the critical communication pathways and cellular circuits necessary for effective anti-tumor immunity. Tumor-infiltrating T cells (TIL) are key mediators of the anti-tumor immune responses. However, chronic exposure to tumor antigens leads to the acquisition of an exhausted phenotype. Here, the authors present a bispecific T-cell engager that combines an anti-TIM-3 antibody with an IFN-α fusion protein (BiDT) and facilitates T cell-dendritic cells (DC) interactions. In preclinical mouse models, the enhanced T cell-DC crosstalk, dependent on CD28 co-stimulation and IL-2 signaling, boosts anti-tumor immunity and the generation of memory T cell responses.

Source: Nature Communications

DOI: 10.1038/s41467-026-70876-4