Manipulating mitochondrial electron flow enhances tumor immunogenicity.
Science
; 381(6664): 1316-1323, 2023 09 22.
Article
en En
| MEDLINE
| ID: mdl-37733872
ABSTRACT
Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Complejo I de Transporte de Electrón
/
Complejo II de Transporte de Electrones
/
Mitocondrias
/
Antígenos de Neoplasias
/
Neoplasias
Límite:
Humans
Idioma:
En
Revista:
Science
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos