Manipulating mitochondrial electron flow enhances tumor immunogenicity

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.

A mitochondria-targeted anticancer copper dithiocarbamate amplifies immunogenic cuproptosis and macrophage polarization

“…5B), which plays a role in the assembly of mitochondrial respiratory chain complex II, aligns with recent research suggesting that complex II deficiency enhances antigen presentation and T cell-mediated killing. 12 In addition, Gene Set Enrichment Analysis (GSEA) demonstrated that TPP-CuET inhibited the cuproptosis target TCA cycle (Fig. 5E), disrupted the mitochondrial inner membrane, and impeded the electron transport chain, thereby substantiating its impact on mitochondrial functions (Fig.…”

“…10,11 The latest study by Mangalhara et al shows that enhanced tumor antigen presentation and T cell-mediated killing can be achieved by manipulating mitochondrial electron flow. 12 Therefore, targeting mitochondrial vulnerabilities emerges as a promising therapy model for cancer therapy. Tsvetkov et al discovered that some copper ionophores, like diethyldithiocarbamate, could bind lipoylated proteins of the (tricarboxylic acid) TCA cycle at mitochondria and induce cuproptosis in cancer cells.…”

ROSALINDprotects the mitochondrial translational machinery from oxidative damage

“…Collectively several lines of evidence support the idea that increased oxidative stress supports tumour initiation an metastatisation 26 however this effect is largely dependent on the genetic and metabolic context 10,26 . Furthermore, high ROS levels contribute to the efficacy of many anticancer drugs 12 and increase cancer cell immunogenicity 22,27 . It is clear therefore that fine tuning of ROS levels can tilt the cell balance between life and death.…”

Blood–Brain Barrier Penetrating Nanovehicles for Interfering with Mitochondrial Electron Flow in Glioblastoma

“…Manipulating the mitochondrial electron transport chain (ETC) enhances tumor immunogenicity, rendering immune-evasive tumors vulnerable to immune surveillance. − Dysfunction of complex II (CII) leads to the abnormal transfer of electrons in the ETC, an increase in succinate production and upregulation of the expression of major histocompatibility complex (MHC) and antigen processing and presentation (APP) genes, making GBM more susceptible to cytotoxic T-cell recognition and elimination. − Moreover, mitochondrial DNA (mtDNA) possesses CpG motifs, making them vulnerable to mitochondrial reactive oxygen species (mtROS). , Here, we synthesized iridium photosensitizer (IrPS) that electrostatically bind to GBM cell mitochondria by the positive charge after illumination by two-photon light, induce ETC damage, and produce mtROS to oxidize mtDNA. Oxidized mtDNA in GBM can activate the STING pathway, thereby enhancing GBM immune responsiveness and subsequently activating both innate and adaptive immunity.…”