Role of mitochondrial alterations in human cancer progression and cancer immunity

Abstract

Dysregulating cellular metabolism is one of the emerging cancer hallmarks. Mitochondria are essential organelles responsible for numerous physiologic processes, such as energy production, cellular metabolism, apoptosis, and calcium and redox homeostasis. Although the "Warburg effect," in which cancer cells prefer aerobic glycolysis even under normal oxygen circumstances, was proposed a century ago, how mitochondrial dysfunction contributes to cancer progression is still unclear. This review discusses recent progress in the alterations of mitochondrial DNA (mtDNA) and mitochondrial dynamics in cancer malignant progression. Moreover, we integrate the possible regulatory mechanism of mitochondrial dysfunction-mediated mitochondrial retrograde signaling pathways, including mitochondrion-derived molecules (reactive oxygen species, calcium, oncometabolites, and mtDNA) and mitochondrial stress response pathways (mitochondrial unfolded protein response and integrated stress response) in cancer progression and provide the possible therapeutic targets. Furthermore, we discuss recent findings on the role of mitochondria in the immune regulatory function of immune cells and reveal the impact of the tumor microenvironment and metabolism remodeling on cancer immunity. Targeting the mitochondria and metabolism might improve cancer immunotherapy. These findings suggest that targeting mitochondrial retrograde signaling in cancer malignancy and modulating metabolism and mitochondria in cancer immunity might be promising treatment strategies for cancer patients and provide precise and personalized medicine against cancer.

Keywords: Cancer immunity; Cancer progression; Mitochondria; Retrograde signaling.

Fig. 1

Mitochondrial alterations and mitochondrial retrograde signaling in cancer progression. Several mitochondrial alterations have been implicated in various types of human cancers. Mitochondrial alteration-induced mitochondrial dysfunction might activate mitochondrial retrograde signaling pathways by mitochondrion-derived molecules (ROS, calcium, oncometabolites, and mtDNA) and mitochondrial stress response pathways (mtUPR and ISR) to promote cancer progression to malignancy. The figure was created with BioRender.com

Fig. 2

The role of mitochondria in cancer immunity. Mitochondria are essential for the immune regulatory function of T cells, macrophages, and NK cells. In T cells, activated T cells might rely more on glycolysis than OXPHOS and are characterized by fission and flabby cristae-type mitochondria. ROS are essential to the activation of T cells. Switching to OXPHOS or fatty acid oxidation might be implicated in the immunosuppressive status. Similarly, proinflammatory macrophages are more dependent on glycolysis and ROS, while increased OXPHOS and fatty acid oxidation might contribute to the differentiation of anti-inflammatory macrophages. NK cells mainly utilize glucose through elevated glycolysis and OXPHOS to support cytokine secretion and maintain cytotoxic activity. A combination of immune checkpoint inhibitors with agents modulating energy metabolism and mitochondria might be a precision and personalized modality for cancer immunotherapy. The figure was created with BioRender.com