S. Yang, A. C. Bader, S. Sendker, A. Hu, D. C. Chen, H. Nath, A. Chen, E. Bobilev, M. Sheffer, V. W. Hui, T. E. Kochs, A. Maia, J. Tang, F. Liu, X. Deng, M. Nguyen, M. Stanojevic, M. Tarannum, C. L. Albert, A. K. Ali, R. Shapiro, Y. Wei, K. Zhang, Z. Wang, Y. R. Chung, E. Parry, M. Campisi, D. Barbie, A. A. Lane, H. Li, K. L. Ligon, K. Huang, K. W. Wucherpfennig, S. Chugh, E. Ullrich, H. Einsele, J. Chen, J. Koreth, V. S. Silveira, R. Soiffer, J. S. Little, C. J. Wu, J. Ritz, J. Li, A. J. Aguirre, R. Romee
Despite advances in immunotherapy, most solid tumors remain resistant to treatment. Immune cell engagers redirect cytotoxic lymphocytes against cancer, but limited tumor access, immunosuppressive microenvironments and systemic immune activation limit efficacy. Here we develop live immune modulating engagers (LIME), a modular platform where non-pathogenic, tumor-tropic Escherichia coli display tandem single-chain variable fragments targeting a tumor-associated antigen and an activating receptor on T or natural killer cells. LIME bridged effector and tumor cells, induced transcriptional programs of T cell activation, metabolism and proliferation, and enhanced cytotoxicity across cancer cell lines and patient-derived organoids. In mouse models, LIME safely accumulated in tumors, outperformed tarlatamab in small cell lung cancer, and induced durable immunity in lymphoma. RAS inhibition and PD-L1 blockade enhanced LIME activity in pancreatic cancer and induced humoral responses. Multi-lineage immune modulation remained tumor-confined, without organ toxicity. These findings establish LIME as a versatile living therapeutic platform for programmable, tumor-restricted immune orchestration.