A cleavable IL10-TCE counteracts TCE-induced T cell dysfunction and eradicates solid tumors without toxicity

The clinical success of T cell engagers (TCEs) in hematologic malignancies has been difficult to replicate in solid tumors due to limited efficacy and on-target toxicities, partly driven by CD3-directed activation-induced cell death (AICD) and exhaustion of tumor-infiltrating lymphocytes (TILs). To overcome T cell dysfunction in the tumor microenvironment, we found that IL-10 receptor expression is enriched on antigen-specific T cells and that exogenous IL-10 markedly reduces T cell death while preserving overall T cell numbers. Guided by this insight, we engineered a series of IL-10-integrated TCE formats and identified an optimized design in which IL-10 is fused to the N-terminus of the anti-CD3 arm in a cleavable configuration, generating a pro-TCE (IL10-TCE) with favorable biochemical properties and potent antitumor activity without detectable toxicity. The IL10-TCE enhanced effector function and substantially expanded both total and antigen-specific T cells within tumors, resulting in complete regression of established solid tumors and metastatic lesions across multiple syngeneic and xenograft models, including colon cancer, melanoma, and pancreatic cancer. These findings establish IL-10 incorporation as a generalizable strategy to overcome TCE-induced T cell dysfunction, enabling robust tumor eradication and durable immune protection.