A dual-tumor-recognition trispecific T-cell nano-engager enhances effector-target conjugation and antitumor activity.

T-cell engagers redirect cytotoxic lymphocytes toward malignant cells, but their efficacy in solid tumors is limited by uneven antigen expression and inefficient effector-target contact. Here, we report a modular dual-tumor-recognition trispecific T-cell nano-engager (Tri-NanoTCE) generated by Fc-mediated assembly of anti-PD-L1, anti-EGFR, and anti-CD3 IgG1 antibodies on an FcγR1-HSA/PLLA nano-adaptor. PD-L1 and EGFR provide complementary tumor recognition and anchoring, whereas CD3 recruits T cells. Tri-NanoTCE retained the binding activity of all antibodies, showed efficient antibody loading, and increased tumor-cell surface association relative to single-target nano-engagers. This dual-recognition design strengthened effector-target conjugation, enhanced CD69 expression, cytotoxic mediator release, and PBMC-mediated tumor-cell killing, and outperformed free antibody mixtures or dual-component controls. In PBMC-reconstituted MDA-MB-231 and A375 xenografts, Tri-NanoTCE prolonged intratumoral retention, increased human T-cell infiltration, and suppressed tumor growth without obvious short-term systemic toxicity. These findings support modular nanoassembly as a materials strategy for constructing trispecific T-cell engagers for antigen-heterogeneous solid tumors, particularly where target coverage and effector contact are limiting.