RESUMO
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.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Camundongos , Animais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Antígeno B7-H1/uso terapêutico , Linhagem Celular Tumoral , Imunoterapia , Modelos Animais de Doenças , Fatores Imunológicos/uso terapêutico , Vacinação , Polietilenoglicóis/uso terapêutico , Microambiente TumoralRESUMO
Different from traditional "always on" photothermal therapy (PTT) agents, tumor microenvironment responsive agents showed more tumor specificity and lower photo-toxicity to normal tissues. Herein, a photo-stable and reversible pH responsive phenazine dye (PIOH) was synthesized and assembled with liposomes forming nanoparticles (PIOH-NPs), which exhibited a strong NIR absorption in a weak acid environment and were successfully utilized for photoacoustic (PA) imaging-guided photothermal therapy in mice.