Systemic Delivery of mPEG‐Masked Trispecific T‐Cell Nanoengagers in Synergy with STING Agonists Overcomes Immunotherapy Resistance in TNBC and Generates a Vaccination Effect

T‐cell engagers (TCEs) represent a breakthrough in hematological malignancy treatment but are vulnerable to antigen escape and lack a vaccination effect. The “immunologically cold” solid tumor presents substantial challenges due to intratumor heterogeneity and an immunosuppressive tumor microenvironment (TME). Here, a methoxy poly(ethylene glycol) (mPEG)‐masked CD44×PD‐L1/CD3 trispecific T‐cell nanoengager loaded with the STING agonist c‐di‐AMP (CDA) (PmTriTNE@CDA) for the treatment of triple‐negative breast cancer (TNBC) is rationally designed. PmTriTNE@CDA shows tumor‐specific accumulation and is preferentially unmasked in response to a weakly acidic TME to prevent on‐target off‐tumor toxicity. The unmasked CD44×PD‐L1/CD3 trispecific T‐cell nanoengager (TriTNE) targets dual tumor‐associated antigens (TAAs) to redirect CD8+ T cells for heterogeneous TNBC lysis while achieving PD‐L1 blockade. PmTriTNE synergized with CDA to transform the cold tumor into a hot tumor, eradicate the large established TNBC tumor, and induce protective immune memory in a 4T1 orthotopic tumor model without causing obvious toxicity. PmTriTNE@CDA shows potent efficacy in cell line‐derived xenograft (CDX) and patient‐derived xenograft (PDX) mouse models. This study serves as a proof‐of‐concept demonstration of a nanobased TCEs strategy to expand therapeutic combinations that previously could not be achieved due to systemic toxicity with the aim of overcoming TNBC heterogeneity and immunotherapy resistance.