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The \u201cimmunologically cold\u201d solid tumor presents substantial challenges due to intratumor heterogeneity and an immunosuppressive tumor microenvironment (TME). Here, a methoxy poly(ethylene glycol)\u00a0(mPEG)\u2010masked CD44\u00d7PD\u2010L1\/CD3 trispecific T\u2010cell nanoengager loaded with the STING agonist c\u2010di\u2010AMP (CDA) (PmTriTNE@CDA) for the treatment of triple\u2010negative breast cancer (TNBC) is rationally designed. PmTriTNE@CDA shows tumor\u2010specific accumulation and is preferentially unmasked in response to a weakly acidic TME to prevent on\u2010target off\u2010tumor toxicity. The unmasked CD44\u00d7PD\u2010L1\/CD3 trispecific T\u2010cell nanoengager (TriTNE) targets dual tumor\u2010associated antigens (TAAs) to redirect CD8+ T cells for heterogeneous TNBC lysis while achieving PD\u2010L1 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\u2010derived xenograft (CDX) and patient\u2010derived xenograft (PDX) mouse models. This study serves as a proof\u2010of\u2010concept 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.<\/jats:p>","DOI":"10.1002\/advs.202203523","type":"journal-article","created":{"date-parts":[[2022,9,11]],"date-time":"2022-09-11T23:31:01Z","timestamp":1662939061000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Systemic Delivery of mPEG\u2010Masked Trispecific T\u2010Cell Nanoengagers in Synergy with STING Agonists Overcomes Immunotherapy Resistance in TNBC and Generates a Vaccination Effect"],"prefix":"10.1002","volume":"9","author":[{"given":"Ming","family":"Shen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes Shanghai Cancer Institute Renji Hospital School of Medicine Shanghai Jiao Tong University 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