Mitochondrial regulation in the tumor microenvironment: targeting mitochondria for immunotherapy

Abstract

Mitochondrial regulation plays a crucial role in cancer immunity in the tumor microenvironment (TME). Infiltrating immune cells, including T cells, natural killer (NK) cells, and macrophages, undergo mitochondrial metabolic reprogramming to survive the harsh conditions of the TME and enhance their antitumor activity. On the other hand, immunosuppressive cells like myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), mast cells, and tumor-associated macrophages (TAMs) rely on mitochondrial regulation to maintain their function as well. Additionally, mitochondrial regulation of cancer cells facilitates immune evasion and even hijacks mitochondria from immune cells to enhance their function. Recent studies suggest that targeting mitochondria can synergistically reduce cancer progression, especially when combined with traditional cancer therapies and immune checkpoint inhibitors. Many mitochondrial-targeting drugs are currently in clinical trials and have the potential to enhance the efficacy of immunotherapy. This mini review highlights the critical role of mitochondrial regulation in cancer immunity and provides lists of mitochondrial targeting drugs that have potential to enhance the efficacy of cancer immunotherapy.

Keywords: TME; immune evasion; immunotherapy; metabolism; mitochondria.

Figure 1

Cancer immune evasion and immunosuppressive cells. Cancer cells exhibit increased glucose uptake and heavily rely on glycolysis through a phenomenon known as the Warburg effect, a form of metabolic reprogramming. This heightened glucose uptake restricts glucose availability for immune cells, while lactate itself suppresses the antitumor activity of immune cells. Cancer cells can hijack mitochondria from T cells via mitochondrial transfer. Various immunosuppressive cells aid in tumorigenesis, and metabolic pathways, such as fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS), adapt depending on the circumstances. NK, natural killer; Tregs, regulatory T cells; MDSCs, myeloid-derived suppressor cells; TAMs, tumor-associated macrophages.