Mitochondrial metabolism and signaling direct dendritic cell function in antitumor immunity

Science. 2026 Apr 2;392(6793):eadv6582. doi: 10.1126/science.adv6582. Epub 2026 Apr 2.

Abstract

Antitumor immunity requires conventional type 1 dendritic cells (cDC1s). How cDC1s maintain functional fitness in the tumor microenvironment remains unclear. In this study, we established that intratumoral cDC1s exhibited discrete mitochondrial states and that OPA1-mediated mitochondrial energy and redox metabolism dictated cDC1 antitumor responses. Mechanistically, OPA1 orchestrated antigen presentation and the CD8+ T cell priming function of cDC1s by promoting nuclear respiratory factor 1 (NRF1) expression and electron transport chain integrity, thereby supporting bioenergetics and NAD+/NADH balance. During tumor progression, mitochondrial membrane potential and volume, as well as OPA1-NRF1 signaling, declined in intratumoral cDC1s. Furthermore, intratumoral administration of cDC1s with polarized mitochondria showed immunotherapeutic benefits in mice, particularly in combination with immune checkpoint blockade. Collectively, our findings reveal mitochondrial metabolism and signaling as putative targets to reinvigorate cDC1 function for cancer immunotherapy.

MeSH terms

  • Animals
  • Antigen Presentation
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Dendritic Cells* / immunology
  • Dendritic Cells* / metabolism
  • Dendritic Cells* / transplantation
  • Energy Metabolism
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • Immunotherapy
  • Membrane Potential, Mitochondrial
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria* / immunology
  • Mitochondria* / metabolism
  • NAD / metabolism
  • Neoplasms* / immunology
  • Neoplasms* / therapy
  • Oxidation-Reduction
  • Signal Transduction
  • Tumor Microenvironment / immunology

Substances

  • Opa1 protein, mouse
  • GTP Phosphohydrolases
  • NAD