Remodeling the hepatic immune microenvironment and demolishing T cell traps to enhance immunotherapy efficacy in liver metastasis.
J Control Release
; 373: 890-904, 2024 Sep.
Article
en En
| MEDLINE
| ID: mdl-39067794
ABSTRACT
Immune checkpoint inhibitors (ICIs) exhibit compromised therapeutic efficacy in many patients with advanced cancers, particularly those with liver metastases. Much of this incapability can be ascribed as an irresponsiveness resulting from the "cold" hepatic tumor microenvironment that acts as T cell "traps" for which there currently lack countermeasures. We report a novel nanomedicine that converts the hepatic immune microenvironment to a "hot" phenotype by targeting hepatic macrophage-centric T cell elimination. Using the nanomedicine, composed of KIRA6 (an endothelium reticulum stress inhibitor), α-Tocopherol nanoemulsions, and anti-PD1 antibodies, we found its potency in murine models of orthotopic colorectal tumors and hepatic metastases, restoring immune responses and enhancing anti-tumor effects. A post-treatment scrutiny of the immune microenvironment landscape in the liver reveals repolarization of immunosuppressive hepatic macrophages, upregulation of Th1-like effector CD4+ T cells, and rejuvenation of dendritic cells along with CD8+ T cells. These findings suggest adaptations of liver-centric immune milieu modulation strategies to improve the efficacy of ICIs for a variety of "cold" tumors and their liver metastases.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Microambiente Tumoral
/
Inmunoterapia
/
Neoplasias Hepáticas
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Control Release
Asunto de la revista:
FARMACOLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Países Bajos