Open AccessSystemic Delivery of mPEG‐Masked Trispecific T‐Cell Nanoengagers in Synergy with STING Agonists Overcomes Immunotherapy Resistance in TNBC and Generates a Vaccination Effect
Author(s) -
Shen Ming,
Chen Chuanrong,
Guo Qianqian,
Wang Quan,
Liao Jinghan,
Wang Liting,
Yu Jian,
Xue Man,
Duan Yourong,
Zhang Jiali
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202203523
Subject(s) - sting , immunotherapy , vaccination , medicine , cancer research , immunology , immune system , engineering , aerospace engineering
Abstract 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.