Abstract T cell engagers (TCEs) have achieved transformative success in B-cell malignancies but show limited efficacy in solid tumors with severe toxicity. Here, we identify insufficient IL-2 signaling as a key bottleneck for sustaining TCE-induced T-cell function. Although exogenous IL-2 enhances TCE efficacy, its systemic administration causes more severe toxicity. To overcome this limitation, we engineered a protease-activatable dual-variable-domain (DVD) as Pro-TCE to reduce its off-tumor toxicity. Furthermore, we designed a mutant IL-2 (3E) with markedly reduced receptor affinity that is inactive in periphery. The construct (DVD-3E) remains inert in circulation and becomes locally activated only upon tumor-specific protease cleavage, coupling T-cell engagement with cis IL-2 signaling. This logic-gated design restricts both TCE and cytokine activity to the tumor microenvironment (TME), enabling potent antitumor responses without systemic toxicity. Mechanistically, DVD-3E enhances the persistence and effector function of preexisting intratumoral T cells, expands TCF1+ progenitor and antigen-specific T cells populations, mitigates exhaustion, and establishes durable immune memory. Notably, DVD-3E treatment increased the frequency of antigen-specific T cells in draining lymph nodes, which were capable of controlling distant tumors and mediating effective tumor regression upon adoptive transfer. These findings define a new design principle for logic gated TCEs that achieve a favorable balance between safety and efficacy, offering a strategy to overcome current therapeutic resistant. Citation Format: Yang-Xin Fu, . Logic-gated T cell engager linked with mutant IL-2 for safer and better effective solid tumor immunotherapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7460.
Y. Fu (Fri,) studied this question.