International Business Department           Liu Bojia           September 22, 2023

  In order to meet rapid growth, cancer cells tend to look for additional sources of energy and regulate their own metabolic processes. In contrast to otherwise normal cells, cancer cells choose glutamine and fatty acids as their main source of nutrition while consuming glucose at an accelerated rate. Some studies have speculated that this metabolic reprogramming process may draw the attention of the immune system, thereby boosting the chances of immune cells clearing tumors.

  For example, mitochondria, which act as energy factories, have been the subject of much research in related fields, and the role of mitochondria remains controversial in different studies, with some suggesting that cancer cells can involve oxygen and sugar in mitochondrial metabolism, but are not particularly dependent on mitochondria for survival.

  In the latest issue of Science, scientists take us back to the role of mitochondria in tumor growth. They also confirm that by fine-tuning mitochondrial metabolism, they can attract the attention of immune cells and clear away tumors.

  Various complexes in the mitochondria perform different functions, with complex 1 and complex 2 regulating and initiating electron transfer and acting as important "gatekeepers" of mitochondrial metabolism. The two complexes also have alternative names for their respective roles: complex 1 is known as NADH dehydrogenase, while complex 2 is known as succinate dehydrogenase, which oxidizes succinic acid to fusaric acid while transferring electrons.

  And it was this specificity of complex 2 that led the team to discover its potential role in resisting tumor growth. First, the authors tried to inhibit the function of each of the two complexes in melanoma cells, and as a result, they found that tumor growth slowed down only when complex 2 was inhibited, while blocking complex 1 had no such effect.

  The key was in the succinic acid, which was no longer converted to fenugreek when complex 2 was blocked. The accumulating succinate disrupts the original balance, and according to the authors' observations, the increase in succinate breaks the ratio of alpha-ketoglutarate to succinate, which inhibits histone demethylase activity.

  This directly stimulates the expression of a number of immune genes in the nucleus of the cell, and in particular can increase the expression of MHC proteins on the surface of tumor cells. Killer T-cells normally rely on these proteins to recognize cancer cells, and the work of the T-cells unfolds more easily when MHC levels are elevated. These aforementioned changes could be reversed by increasing the levels of alpha-ketoglutarate, which again confirms that the ratio between the two molecules becomes a key factor between metabolism and tumor immunity.

  Dr. Kailash Mangalhara, the first author of the study, said that this also suggests that mitochondrial activity determines how susceptible a tumor is to being recognized by the immune system. This is a novel mechanism, and by controlling some of these steps, the researchers were able to regulate the efficiency with which cancer cells are removed by the immune system.

  Of course, it's not practical to directly block the activity of mitochondrial complex 2, as this would disrupt mitochondrial function in normal cells. But they found that there is a protein called MCJ that interacts with complex 1, thus increasing the electrons that pass through complex 1 and decreasing the activity of complex 2 in disguise.

  This increases the accumulation of tumor succinic acid, which allows the immune system to pay more attention to the presence of cancer cells, boosting the efficiency of anti-cancer treatments such as immunotherapy.