# Tumour immunogenicity goes with the (mitochondrial electron) flow

## TL;DR

Blocking a part of the mitochondria's energy system boosts the immune system's ability to fight tumors by increasing their visibility to immune cells.

## Contribution

The study reveals a novel mechanism where mitochondrial complex II inhibition enhances tumor immunogenicity via succinate-induced histone methylation changes.

## Key findings

- Inhibiting complex II increases tumor immunogenicity and T-cell cytotoxicity.
- Succinate accumulation alters histone methylation, upregulating MHC-APP genes independently of interferon signaling.
- This approach may benefit tumors with low MHC-APP expression or impaired interferon signaling.

## Abstract

Mitochondrial metabolism and electron transport chain (ETC) function are essential for tumour proliferation and metastasis. However, the impact of ETC function on cancer immunogenicity is not well understood. In a recent study, Mangalhara et al. found that inhibition of complex II leads to enhanced tumour immunogenicity, T‐cell‐mediated cytotoxicity and inhibition of tumour growth. Surprisingly, this antitumour effect is mediated by succinate accumulation affecting histone methylation. Histone methylation promotes the transcriptional upregulation of major histocompatibility complex–antigen processing and presentation (MHC‐APP) genes in a manner independent of interferon signalling. Modulating mitochondrial electron flow to enhance tumour immunogenicity provides an exciting new therapeutic avenue and may be particularly attractive for tumours with reduced expression of MHC‐APP genes or dampened interferon signalling.

Mitochondrial electron transport chain is required for tumour proliferation and T‐cell immune responses. However, the relationship between mitochondrial metabolism, tumour growth and immunogenicity remains unclear. Mangalhara et al. show that modulating mitochondrial electron flow by inhibition of complex II induces succinate accumulation that results in increased tumour immunogenicity and cytotoxic T‐cell activation leading to reduced tumour growth.