Triple-Combination Immunogenic Nanovesicles Reshape the Tumor Microenvironment to Potentiate Chemo-Immunotherapy in Preclinical Cancer Models.
Adv Sci (Weinh)
; 10(15): e2204890, 2023 05.
Article
em En
| MEDLINE
| ID: mdl-37017572
ABSTRACT
Immune checkpoint blockade (ICB) therapies have had a tremendous impact on cancer therapy. However, most patients harbor a poorly immunogenic tumor microenvironment (TME), presenting overwhelming de novo refractoriness to ICB inhibitors. To address these challenges, combinatorial regimens that employ chemotherapies and immunostimulatory agents are urgently needed. Here, a combination chemoimmunotherapeutic nanosystem consisting of a polymeric monoconjugated gemcitabine (GEM) prodrug nanoparticle decorated with an anti-programmed cell death-ligand 1 (PD-L1) antibody (αPD-L1) on the surface and a stimulator of interferon genes (STING) agonist encapsulated inside is developed. Treatment with GEM nanoparticles upregulates PD-L1 expression in ICB-refractory tumors, resulting in augmented intratumor drug delivery in vivo and synergistic antitumor efficacy via activation of intratumor CD8+ T cell responses. Integration of a STING agonist into the αPD-L1-decorated GEM nanoparticles further improves response rates by transforming low-immunogenic tumors into inflamed tumors. Systemically administered triple-combination nanovesicles induce robust antitumor immunity, resulting in durable regression of established large tumors and a reduction in the metastatic burden, coincident with immunological memory against tumor rechallenge in multiple murine tumor models. These findings provide a design rationale for synchronizing STING agonists, PD-L1 antibodies, and chemotherapeutic prodrugs to generate a chemoimmunotherapeutic effect in treating ICB-nonresponsive tumors.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Microambiente Tumoral
/
Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article