{"id":2623,"date":"2026-02-15T13:55:34","date_gmt":"2026-02-15T04:55:34","guid":{"rendered":"https:\/\/staging.healthist.net\/en\/?p=2623"},"modified":"2026-03-10T19:16:21","modified_gmt":"2026-03-10T10:16:21","slug":"special-feature-1-the-impact-of-mitochondria-cancer-cells-suppress-t-cells-by-means-of-mitochondrial-hijack","status":"publish","type":"post","link":"https:\/\/healthist.net\/en\/medicine\/2623\/","title":{"rendered":"Special Feature 1 – The Impact of Mitochondria <\/small>Cancer cells suppress T cells’ function by means of mitochondrial “hijack”"},"content":{"rendered":"

I have reported that mitochondria in cancer cells are transferred into surrounding T cells, where they inhibit T cells’ function as immune cells and, as a result, suppress the effects of cancer immunotherapy.<\/p>\n

I was originally a clinician specializing in lung cancer. During my time in that field, I saw firsthand how the effects of gefitinib (brand name: Iressa) differed from one patient to another, and learned that EGFR gene mutations had been found in tumors with a marked response. As I had seen for myself the major differences in the effects of cancer immunotherapy, and data indicative of this point had emerged in a number of articles as well, the question of why such variations occurred lingered powerfully in my mind.<\/p>\n

Mitochondria hindered genome analysis<\/h2>\n

Immune checkpoint inhibitors were first commercialized in the early 2010s. Nivolumab (brand name: Opdivo) went on sale in 2014, with its range of indications expanding thereafter. However, even here, the effects varied from one patient to another, so I embarked on research aimed at eliminating the questions I had had since my days as a clinician.<\/p>\n

When I first began my cancer immunity research, I belonged to a laboratory researching regulatory T cells, so I was able to pursue studies using human specimens. I believe this to be one reason why my later articles met with favorable evaluation. By the time I left that laboratory to pursue independent research, a fair amount of time had passed since nivolumab’s launch and there had been quite a few studies on the differences in its effects, as well as efforts to explore blood biomarkers for measuring those differences. As such, I wondered whether there might be a research topic with greater originality.<\/p>\n

At any rate, it was just then I heard about mitochondrial dysfunction in the T cells of cancer patients, and about the possibility of mitochondrial transfer. In addition, one of my friends was a researcher working on clonal hematopoiesis, and the fact I had often heard him talk about his work was also a catalyst for my decision to focus on gene mutations in T cells surrounding cancer cells. Clonal hematopoiesis is the phenomenon in which hematopoietic (blood-forming) cells with gene mutations proliferate vigorously, and may eventually lead to leukemia and other diseases.<\/p>\n

As might be expected, most research focused on DNA in the cell nucleus rather than mitochondria. Numbering anywhere from hundreds to thousands in a single cell, mitochondria are a hindrance to what is termed genomic (nuclear DNA) analysis, so data relating to them were often discarded. It was perhaps fortunate for me that I myself had limited knowledge of mitochondria, as I decided to try analyzing mitochondrial DNA and, when I began my observations, I discovered the same DNA mutations in T cell mitochondria as in cancer cell mitochondria. That was back in 2021.<\/p>\n

Cancer cells and T cells share common mutations<\/h2>\n

In an experiment, we stained cancer cell mitochondria red and T cell mitochondria green. When we cultured these cells together, the T cell mitochondria turned yellow. The yellow is created by the mixture of red and green. In this situation, both types of mitochondria coexisted, but some cells turned completely red. The fact that they turned red means we can say that the mitochondria in the T cells were replaced by those of the cancer cells (Figure 1). Our initial hypothesis that mitochondria might be transferred grew closer to certainty, as we observed that the cancer cells and surrounding T cells shared the same mutations.<\/p>\n

\"\"<\/small><\/p>\n

Figure 1. <\/span>Mitochondrial transfer<\/span><\/strong>The red mitochondria from the cancer cells move into the T cells and mix with the green mitochondria, turning them yellow; in some cases, the green mitochondria are replaced by red.<\/p>\n<\/div>\n

So, how does this mitochondrial transfer occur?<\/p>\n

There are two main types of mitochondrial transfer (Figure 2). In the first method, a cell comes into contact with a recipient cell and grows a tube-like structure (tunneling nanotube, or TNT) through which the mitochondria travel. In the second method, mitochondria enter exosomes or other extracellular vesicles secreted when the cell fragments, and travel in these. There also appear to be cases in which macrophage-like cells grow tubes through which they send mitochondria into cancer cells. Perhaps because of such observations, there were many reports suggesting that cancer was activated by the supply of something from the surrounding cells to the cancer, whereas reports indicating transfer from cancer cells to surrounding cells were not predominant.<\/p>\n

\"\"<\/small><\/p>\n

Figure 2. <\/span>Mechanism of mitochondrial transfer<\/span><\/strong>TNT extend from both T cells and cancer cells, through which mitochondria are transferred; mitochondria also transferred via extracellular vesicles.<\/p>\n<\/div>\n

However, we did not imagine that cancer cells and their mitochondrial DNA would harbor mutations of some kind. Mutation is a phenomenon principally found in cancer cells; if the same mutation is found in a cancer cell and a T cell, it is only natural to conclude that the mutation originated in the cancer.<\/p>\n

If a supply of normal mitochondria from surrounding T cells were beneficial to cancer cells, the mitochondrial DNA of cancer cells should be wild-type, but around 40% of the actual specimens showed high-frequency mutations in the mitochondrial DNA of cancer cells.<\/p>\n

Mitochondria are transferred from cancer cells to T cells and vice versa, but we observed that few of the mitochondria transferred from normal cells to cancer cells survived. This might be because they are exposed to substantial oxidative stress within the cancer cells.<\/p>\n

Mitophagy is inhibited in cancer cells<\/h2>\n

The hardest part of this study was demonstrating why mitochondria in T cells are replaced by those from cancer cells and why such a process can occur.<\/p>\n

One conceivable reason is the powerful oxidative stress within cancer cells. Under normal circumstances, mitochondria are eliminated by means of mitophagy (mitochondrial autophagy) when subject to oxidative stress. However, we hypothesize that the fact that cancer cell mitochondria survive amid the powerful oxidative stress in those cells means that those mitochondria are resistant to oxidative stress, and that mitophagy is inhibited in cancer cells.<\/p>\n

We also believe that when these resistant mitochondria are transferred to surrounding T cells, a mitochondrial “hijack” occurs. That is to say, even if normal mitochondria are eliminated through mitophagy, causing their numbers to decline, the mitochondria derived from cancer cells survive and replace the normal mitochondria.<\/p>\n

Once the normal mitochondria are replaced, T-cell function dramatically declines, causing the T cells to age and become unable to survive for long. The drop in the effectiveness of cancer immunotherapy in this situation has been confirmed in experiments using specimens from both mice and humans. In addition, when we examined specimens from patients who had received immune checkpoint inhibitor therapy without undergoing chemotherapy, we found that the effectiveness of cancer immunotherapy did not last long in patients whose cancer cells harbored mitochondrial DNA mutations, and that their survival rates also fell (Figure 3).<\/p>\n

\"\"<\/small><\/p>\n

Figure 3. <\/span>Association between immune checkpoint inhibitor effectiveness and mitochondrial DNA mutations<\/span><\/strong>The duration of response in patients treated with anti-PD-1 therapy was significantly shorter in the group with mitochondrial DNA mutations.<\/p>\n<\/div>\n

This study also showed that mutated cancer cell mitochondria are transferred to surrounding T cells, where they replace the original mitochondria and consequently reduce the effectiveness of cancer immunotherapy. However, we feel that there are still a number of mysteries surrounding the relationship between mitochondrial mutations and cancer.<\/p>\n

First of all, there is the question of whether mitochondrial DNA mutations are beneficial to cancer cells.<\/p>\n

Some previously reported studies have focused on cells in which mitochondrial DNA mutations have been induced. In essence, they suggested that the mutation of mitochondrial DNA increases oxidative stress within the cell, making metastasis more likely. We, too, conducted experiments using these cells, as well as in mice, and did indeed observe that cells with mutations in their mitochondrial DNA were more prone to metastasize. However, at the same time, cancer cell growth slows considerably. One could say that this is a natural consequence of the fact that mitochondria are responsible for energy production in cells. Although slower growth is a negative phenomenon for cancer cells, it does, on the other hand, have a positive aspect in terms of making metastasis easier. The emergence of mutations in mitochondrial DNA is probably disadvantageous from the perspective of cancer cell growth and proliferation, but even so, we are left with the question of why mitochondria with mutations become predominant.<\/p>\n

For example, if there were 1,000 mitochondria in a lung epithelial cell, at least initially only one would carry a mutation—in other words, one in 1,000. This abnormal mitochondrion should be removed by means of mitophagy, so it is inconceivable that it could take over the cell; however, in cancer cells, such mitochondria go on to predominate.<\/p>\n

A phenomenon called the Warburg effect was reported around 100 years ago. This is the observation that, whereas ordinary cells produce adenosine triphosphate (ATP) via mitochondrial respiration in an oxygen-rich environment, cancer cells use the glycolytic pathway rather than mitochondrial respiration, for some reason, even in oxygen-rich environments.<\/p>\n

The glycolytic pathway is a primitive method of producing ATP, with a production efficiency less than one-fifteenth that of mitochondrial respiration. However, it may have advantages, namely a rapid reaction rate and the generation of nucleic acids and lipids in the ATP production.<\/p>\n

I stated above that, as a result of the self-cleansing system that is mitophagy being inhibited and ceasing to function in cancer cells, it became impossible to eradicate mutated mitochondria. However, mitochondrial mutations themselves might actually benefit cancer cells through such aspects as the speed of the energy production and the generation of other substances. No clear answers have emerged as yet.<\/p>\n

The full range of molecules involved remains unknown<\/h2>\n

Besides this issue, there are no hotspots for mitochondrial DNA mutations. The term “hotspot” refers to DNA regions where mutations are concentrated. In the context of cancer mutations, it means that once a mutation arises in a region advantageous to proliferation, similar mutations will swiftly increase. There are hotspots in the EGFR and KRAS genes, which promote cell proliferation and are known to be associated with cancer. If mitochondrial DNA mutations conferred an advantage to cancer cells, one would expect mutation hotspots, but mitochondrial DNA mutations are comparatively evenly distributed.<\/p>\n

We do not currently know what impact each individual mutation in the mitochondrial DNA of T cells has. Accordingly, although we reported that there were mutations when compared with the wild type, one cannot deny the possibility that there is no functional impact, even if mutations are actually present.<\/p>\n

In this report, we stated that the mitophagy function of T cells was inhibited and that mutated mitochondria came to predominate. But the question is, how is that function inhibited?<\/p>\n

We reported that mitophagy does not readily occur even when mitochondria from cancer cells enter T cells, whereas the original T cell mitochondria are affected by mitophagy because they are normal, and, as a result, mitochondria derived from cancer cells become predominant in environments with strong oxidative stress. In our article, we were able to present data on this phenomenon early on, but we still do not understand why this phenomenon occurs, and the full range of specific molecules involved remains unknown. We are currently exploring potential factors.<\/p>\n

In our report, we obtained our findings by observing human specimens, with a focus on mitochondria, but I believe there are various ways in which we could develop upon this work, such as examining whether mitochondrial DNA transfer from cancer cells occurs in other immune cells. We hope that future research, from the perspective of mitochondria harboring cancer cell-derived DNA mutations, will expand in ways that enhance the effectiveness of cancer immunotherapy.<\/p>\n

(Figures courtesy of Yosuke Togashi)<\/small><\/div>\n","protected":false},"excerpt":{"rendered":"

The mechanisms by which cancer cells transfer mitochondria into T cells and replace the T cells’ healthy mitochondria are being elucidated. A subsequent study is now starting to reveal the specific mechanisms involved. At the same time, fresh puzzles have come to light. For example, if mitochondrial DNA mutates, energy production within cells naturally diminishes, slowing the growth of the cancer cells and thus disadvantaging them. As a number of other questions have yet to be explained, research into mitochondria derived from cancer cells continues to warrant close attention.<\/p>\n","protected":false},"author":2,"featured_media":2622,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[14],"tags":[106],"class_list":["post-2623","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-medicine","tag-regulatory-t-cells"],"acf":{"author":"composition by Rie Iizuka
illustration by Koji Kominato","intro":"

The mechanisms by which cancer cells transfer mitochondria into T cells and replace the T cells’ healthy mitochondria are being elucidated. A subsequent study is now starting to reveal the specific mechanisms involved. At the same time, fresh puzzles have come to light. For example, if mitochondrial DNA mutates, energy production within cells naturally diminishes, slowing the growth of the cancer cells and thus disadvantaging them. As a number of other questions have yet to be explained, research into mitochondria derived from cancer cells continues to warrant close attention.<\/p>","person":[{"acf_fc_layout":"personcontent","personimg":2621,"personsholder":"Professor, Department of Tumor Microenvironment, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University","personname":"Yosuke Togashi","persondetail":"After graduating from the Medical Science Division at Kyoto University’s Faculty of Medicine in 2006, he joined Sumitomo Hospital. In 2009, he became a physician at Kyoto University Hospital. In 2011, he was appointed an assistant professor at Kyoto University’s Graduate School of Medicine. In 2012, he entered the doctoral program at Kindai University’s Graduate School of Medical Sciences, successfully completing it early in 2015. He subsequently served as an assistant professor at Kindai University’s Faculty of Medicine and, after holding a Japan Society for the Promotion of Science Research Fellowship for Young Scientists, as a researcher at the National Cancer Center Japan. He was then appointed as a division head at Chiba Cancer Center Research Institute before taking up his current post in 2021. Since September 2024, he has concurrently served as a professor in the Department of Respiratory Medicine at Okayama University Hospital."}],"issue":2593,"custom_css":""},"_links":{"self":[{"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/posts\/2623","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/comments?post=2623"}],"version-history":[{"count":0,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/posts\/2623\/revisions"}],"acf:post":[{"embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/issue\/2593"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/media\/2622"}],"wp:attachment":[{"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/media?parent=2623"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/categories?post=2623"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/healthist.net\/en\/wp-json\/wp\/v2\/tags?post=2623"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}