LARS2 reprograms mitochondrial metabolism and epigenetically upregulates MHC-I to boost antitumor immunity in nasopharyngeal carcinoma

Abstract

Background Nasopharyngeal carcinoma (NPC) is considered a typical “hot” tumor, yet its immune evasion mechanisms remain poorly defined, and immunotherapy efficacy is suboptimal. Attenuation of intrinsic tumor cell immunogenicity to evade T cell recognition and cytotoxicity represents a major route of tumor immune evasion, whose mechanistic basis is largely unelucidated. Methods Multiplex immunofluorescence and immunohistochemistry were used to assess correlations between mitochondrial leucyl-transfer RNA synthetase 2 (LARS2) expression, CD8+ T cell infiltration and immunotherapy response in NPC tissues. In vitro CD8+ T cell co-cultures, immunodeficient nude mice and immunocompetent murine models were used to explore LARS2-dependent CD8+-mediated antitumor immunity. Blue native polyacrylamide gel electrophoresis (BN-PAGE), extracellular flux and other mitochondrial functional assays were performed to characterize the roles of LARS2 and leucine in electron transport chain (ETC) translation and oxidative phosphorylation (OXPHOS) activity. Chromatin immunoprecipitation-quantitative PCR, ELISA and flow cytometry analyzed epigenetic modifications, major histocompatibility complex class I (MHC-I) expression and antigen presentation. Leucine supplementation combined with anti-programmed cell death protein-1 (PD-1) therapy was tested in mouse models to evaluate in vivo therapeutic efficacy against NPC immune escape. Results We demonstrated that LARS2, a gene mapped to the 3p21 chromosomal region, was significantly downregulated in NPC, and its expression is positively correlated with patient prognosis and response to immunotherapy. Through in vitro and in vivo experiments, we demonstrated that restoration of LARS2 expression accelerates the translation of mitochondrial ETC subunits, enhances OXPHOS, and upregulates MHC-I expression via an epigenetic mechanism. These effects work together to enhance tumor antigen presentation and augment CD8+ T cell-mediated cytotoxicity. Furthermore, we demonstrated that a high-leucine diet increases LARS2 expression and improves the effectiveness of anti-PD-1 immunotherapy. Conclusions This study uncovers a novel mechanism by which the tumor suppressor LARS2 inhibits immune evasion in NPC through upregulation of MHC-I, and highlights a high-leucine diet as a promising strategy to sensitize tumors to immunotherapy.