A modular Multi-Antigen T Cell Hybridizers (MATCH) platform enables tunable and potent immunotherapy across hematologic and solid tumors

T cell-engaging immunotherapies have demonstrated remarkable efficacy in cancer treatment but remain constrained by antigen heterogeneity, immune escape, and dose-limiting toxicities. Here, we present Multi-Antigen T Cell Hybridizers (MATCH), a modular immune-engager platform that decouples tumor recognition from immune activation through programmable molecular hybridization, enabling tunable multi-antigen targeting without permanent multispecific antibody engineering. For multiple myeloma (MM) and acute myeloid leukemia (AML), we developed BCMA- and CD33-directed MATCH systems consisting of tumor-targeting antibody fragments conjugated to a 25-base morpholino oligonucleotide MORF1 (Fab' BCMA -MORF1 or Fab' CD33 -MORF1) and a complementary CD3-engaging T cell module conjugated to complementary MORF2 (Fab' CD3 -MORF2). Hybridization between MORF1 and MORF2 brings tumor cells and T cells into close proximity, facilitating efficient immune synapse formation. Both BCMA and CD33 MATCH induced potent, antigen-dependent cytotoxicity against multiple cancer cell lines and primary patient samples at nanomolar concentrations. Importantly, because the ratio of tumor-targeting and immune-engaging components can be independently adjusted, cytokine release was precisely controlled through sequential versus premixed administration and dose modulation, demonstrating improved tunability compared with conventional bispecific T cell engagers. Cytokine secretion followed a regulated temporal sequence, including IL-2, TNF-alpha, IFN-gamma, and IL-6. In a humanized NRG MM model, T cell dosing was optimized to control graft-versus-host effects, and MATCH treatment significantly prolonged survival compared with untreated controls. Efficacy was also demonstrated in solid tumors, including breast and lung cancers, with PD-L1-targeted MATCH treatment. Beyond CD3-mediated T cell redirection, MATCH enables modular incorporation of costimulatory signaling via Fab' CD28 -MORF2. The combined PD-L1/CD3/CD28 trispecific MATCH configuration significantly enhanced T cell activation and tumor cell killing compared with CD3 engagement alone, achieving up to a 20-fold reduction of IC 50 values, particularly at low antigen density and immunosuppressive conditions characteristic of solid tumors. Activation of tumor cell apoptotic pathways and T cell activation signaling pathways was confirmed. Collectively, these findings establish MATCH as a versatile immune-engager platform capable of addressing both hematologic and solid tumors through programmable antigen targeting and modular immune activation.