How To Damage Your Immune System and Let Cancer Run Wild
Immune therapy is becoming a leading approach to treat cancer. Does it make sense to break your immune system?
Introduction
“The most recent American Dietary Guidelines (2020–2025) recommend shifting dietary fats from solid saturated fats to unsaturated oils. Dietary oils contain different compositions of unsaturated fatty acids (UFA). Oleic acid (OA) and linoleic acid (LA) are the most common UFA in dietary oils. How individual UFA in oils regulate immune cell function and cancer risk remains unclear.” (Jin 2021—all quotes from this source in Bold and Italic.)
This is certainly a neat paper.
Going all the way back to the 1960s, it’s been observed that there was a connection between increased consumption of seed oils and increased rates of cancer. Immigrants to the U.S. often see an increased rate of certain types of cancer (breast and colon, for instance), until their cancer risk ultimately matches the American population.
And it’s well recognized that the seed oil metabolite 4-HNE can cause mutations, notably to the P53 tumor-suppressor gene, especially in colon and liver cancer.
See this post for a model where our favorite obesogenic rodent diet, D12492, causes liver tumors.
When I first started reading about nutrition and disease, there was an English researcher, Barry Groves, who stated that early organ-transplant surgeons had used seed oils to suppress the immune systems of patients, but had to stop because of the increased rates of cancer they saw.
“But the transplant doctors were then astonished to see how quickly their patients developed cancers and the treatment was stopped.” (Groves, 2007)
It’s certainly true that immune suppression causes increased rates of cancer in transplant patients.
“The most significant cancer-related risk for organ transplant recipients, however, is associated with the very immunosuppressive medications that are required to prevent rejection of the organs but also can render the immune system less able to identify and kill tumor cells or battle cancer-linked infections….
A 30-year cohort study in Finland that examined roughly 6500 transplant recipients, for example, found that nearly 1 in 4 eventually contracted cancer; this translated to a 3.6-fold higher risk. For non-melanoma skin cancers, such as basal cell and squamous cell carcinomas, the rate is even higher: Studies have documented anywhere from a 25- to 250-fold increase in risk.” (Nelson, 2025)
But I had never seen a paper demonstrating what the mechanism might be for seed oils impeding immune function, until now.
Linoleic vs. Oleic
This is just what we want to see. A pretty straight-forward bake-off.
They’re using three diets, low-fat (LFD) with 10% soybean oil, a linoleic acid diet (Safflower) with 10% soybean oil and 35% safflower oil, and an oleic acid diet (Olive) with 10% soybean and 35% olive oil
They even give us the fatty-acid composition of the two added oils. Safflower has a lot more LA than even a high-LA olive oil would, so it’s a clear delineation. (In the graphs to follow, Safflower or LA are red. 18:2 is LA, 18:1 is OA.)
Remember, the body makes saturated and monounsaturated fats in the proportions in which they are needed, and so the LFD diet is effectively a lower-LA diet, with the SFA and MUFA made from carbs and the Ω-3 in soybean oil.
They do tell us the effect of the diets on the mice in terms of body weight:
The higher-LA diet produces more obesity in this model, but neither curve looks like what you would get with D12492. Visceral fat is also higher in Safflower as one would expect, but insulin is a smidge lower, which Peter (Hyperlipid) will appreciate.
Safflower Kills Cancer-Killing Cells
We have a variety of white blood cells, and two of them are the T cells, CD8 and CD4. They’re like a sniper team: CD8 is the killer, and CD4 is the spotter, or helper cell, as it’s known. These cells are produced in the thymus, and then released into the general circulation. They go through a period where they are “naive”, which is to say they’ve not been assigned something to kill.
One of the things that these cells can kill is cancer cells. In fact, in several types of cancer better survival is associated with higher numbers of these cells. In HIV, a higher ratio of killer to helper cells is associated with a lower incidence of cancer.
So it seems that killing these cells would be a bad thing.
Sure enough, Safflower kills off the T cells, both as they’re developing in the thymus and after they’re released while they’re still naive.
Fewer Killer Cells Means More Cancer Cells
This isn’t an ideal model. The mice don’t get cancer in this model, they’re given it. They implant E0771 breast cancer cells into the mammary tissue of the three groups of mice, and see how they do.
“…We observed a significant acceleration of mammary tumor growth in the safflower oil–fed mice compared with the olive oil–fed or LFD-fed mice (Fig. 3A).”
And they note that it wasn’t just obesity that was driving tumor growth.
“This observation of uncoupling obesity from tumor growth in mice on the olive oil diet suggests that not all dietary oil-induced obesity is tumorigenic.”
You’ll note that Olive is a smidge higher than LFD, as one would expect from the higher LA percentage.
Fewer Killer Cells, and Weaker Too
After COVID, we’ve all heard of cytokines. Tumor Necrosis Factor Alpha (TNFa) is a cytokine that is produced by CD8 cells, and it is an anti-cancer drug, to oversimplify things. It can cause cancer cells to die (via apoptosis, a controlled cell death) and it also damages the blood cells that feed the tumor.
Unfortunately, Safflower also reduces production of TNFa.
“In line with in vivo data collected from safflower oil–fed or olive oil–fed mice, LA, but not OA induced significant death of CD8+ and CD4+ T cells (Fig. 4A and B). Intracellular staining showed that LA treatment in vitro significantly inhibited the production of TNFa…”
“Altogether, our data indicate that LA in safflower oil–fed mice and in culture negatively affect naive T-cell survival and TNFa production.”
Having your T cells unable to make an anti-tumor chemical is unfortunate.
How Did The T Cells Die?
There are basically three pathways describing how cells die (assuming it’s not from physical injury, like a wound). They are apoptosis, mentioned previously; necrosis, an uncontrolled cell death where the contents of the cells often escape into the general circulation; and ferroptosis, which is defined (erroneously, I think) as an iron-dependent type of cell death.
Next they gave T cells three chemicals which prevent each of the three types of cell death, and then exposed them to LA or OA.
Apoptosis, it turns out, is the culprit.
LA caused an increase in Reactive Oxygen Species (ROS) in the cells. N-acetylcysteine (NAC) is a ROS inhibitor. It is a precursor for glutathione, the most powerful antioxidant in the body.
As you can see, NAC almost totally inhibited the lethality of LA in both CD4 and CD8 T cells. Now here’s the crux of the analysis.
“LA impairs T-cell responses by promoting mitochondrial dysregulation….
“Interestingly, when we measured the production of mitochondrial ROS (Mitosox) in T cells treated with LA, OA, or BSA, we found that LA treatment significantly promoted mitochondrial ROS production in both CD8+ T and CD4+ cells compared with BSA or OA-treated groups (Fig. 5A–C). In line with increased mitochondrial ROS production, LA treatment increased mitochondria, but did not affect peroxisomes in T cells (Fig. 5D). In contrast, OA treatment did not induce significant increase of mitochondria in CD8+ and CD4+ T cells (Fig. 5E and F).
This suggests to me that the mitochondria are trying to compensate for LA-induced damage via lipid peroxidation (fats going rancid), but OA does not induce damage or the need to adapt to it.
Cardiolipin (CL) is a unique fat structure that’s only found in mitochondria, and is an essential part of the energy generation function of the electron transport chain.
“Given that 18:2 LA was the predominant composition of CL, a unique class of phospholipids in mitochondrial inner membrane, and 18:2 LA was more sensitive to ROS-mediated lipid peroxidation than 18:1 OA, we postulated that treatment with LA, but not OA, would induce mitochondrial lipid peroxidation. Indeed, 4-HNE, a common byproduct of lipid peroxidation, was significantly upregulated in both CD8+ and CD4+ T cells in response to LA treatment (Fig. 5G–I). These data demonstrated that LA specifically induced mitochondrial ROS and lipid peroxidation, thus leading to mitochondrial dysfunction in T cells.”
4-HNE is of course only produced from Ω-6 fats, and is highly toxic to cells.
We saw a similar destruction of mitochondria upon seed oil consumption in this study.
Since N-acetyl-L-cysteine (NAC) is an important antioxidant that neutralizes ROS and is a scavenger of α,β-unsaturated aldehydes, we used it to abolish the formation of 4-HNE adducts…. The data indicated that NAC is a reliable 4-HNE-scavenging agent. (Manea, 2015)
“Scavenging” means it removes 4-HNE, and its ability to do damage; and allows it to be excreted harmlessly.
It’s known that 4-HNE is produced from high-LA cardiolipin (Liu, 2011), and that oxidized LA in cardiolipin induces apoptosis (Kagan, 2005).
So the pathway appears to be: increased LA → increased LA in cardiolipin → iron-catalyzed peroxidation of cardiolipin → production of 4-HNE → inducement of apoptosis.
“…CL was the only mitochondrial phospholipid that underwent peroxidation during apoptosis.” (Kagan, 2005)
I’m rather pleased with this finding, as this was exactly the pathway that I described back in 2016:
Blocking Linoleic Acid Prevents T Cell Death and Impedes Tumor Growth
Fatty Acid Binding Protein (FABP) is a protein that transports fats like LA or OA into the cell. E-FABP is a version that is found in large number in T cells.
T cells from mice without E-FABP (E-FABP-/-) are unable to take up LA when cultured with it. This causes several changes to the cell, including a reduction in uncoupling protein 2 (UCP2), which is part of the LA disposal pathway.
“Importantly, E-FABP deficiency significantly reduced mitochondrial lipid peroxidation in T cells (Fig. 6K). Accordingly, LA-induced T-cell death in [wild-type] T cells was significantly reduced when E-FABP was absent (Fig. 6L).”
I discussed disposal of LA as an indication of its toxicity and UCP as a disposal pathway in this post.
Next they fed E-FABP genetic knock-out mice Safflower to see what would happen. This genetic modification did not protect from obesity, but they did have higher levels of CD8 and CD4 T cells, and those cells were able to produce more TNFa than the unmodified mice were.
Then they injected mice with and without E-FABP with breast cancer cells, as above. Mice without E-FABP had a 50% lower tumor load than normal mice.
“These results clearly demonstrated that E-FABP expression in CD8+ T cells was critical in mediating safflower oil-impaired T-cell responses.”
Conclusion
Given:
The many similarities between mice and men when it comes to the effects of seed oil consumption.
The demonstrated increase of certain types of cancer when people immigrate to a high-seed-oil-consumption country like the U.S.
The demonstrated effect impairing immune-system function has on cancer incidence in humans.
It seems wise to avoid seed oils to reduce the risk of cancer.
For the first time, I can also conclude that if you have cancer, elimination of seed-oil consumption should be a first-order alteration to diet, as the potential increase of killer T cells could help fight the disease.
Sadly this also implies that the diet offered in hospitals, in which seed oils are the primary source of fat, should be considered a cancer-promoting diet.
“Dietary Fats High in Linoleic Acids Impair Antitumor T-cell Responses by Inducing E-FABP–Mediated Mitochondrial Dysfunction” (Jin, 2021
References
Groves, Barry. 2007. “Immunity to Infections: Part 2: Polyunsaturated Fats Suppress The Immune System.” Blog. Second Opinions, February 20. http://www.second-opinions.co.uk/immunity2.html.
Jin, Rong, Jiaqing Hao, Yanmei Yi, et al. 2021. “Dietary Fats High in Linoleic Acids Impair Antitumor T-Cell Responses by Inducing E-FABP–Mediated Mitochondrial Dysfunction.” Cancer Research 81 (20): 5296–310. https://doi.org/10.1158/0008-5472.CAN-21-0757.
Kagan, Valerian E., Vladimir A. Tyurin, Jianfei Jiang, et al. 2005. “Cytochrome C Acts as a Cardiolipin Oxygenase Required for Release of Proapoptotic Factors.” Nature Chemical Biology 1 (4): 4. https://doi.org/10.1038/nchembio727.
Liu, Wei, Ned A. Porter, Claus Schneider, Alan R. Brash, and Huiyong Yin. 2011. “Formation Of 4-Hydroxynonenal From Cardiolipin Oxidation: Intramolecular Peroxyl Radical Addition And Decomposition.” Free Radical Biology & Medicine 50 (1): 166–78. https://doi.org/10.1016/j.freeradbiomed.2010.10.709.
Manea, Adrian, Simona-Adriana Manea, Andra Todirita, et al. 2015. “High-Glucose-Increased Expression and Activation of NADPH Oxidase in Human Vascular Smooth Muscle Cells Is Mediated by 4-Hydroxynonenal-Activated PPARα and PPARβ/Δ.” Cell and Tissue Research 361 (2): 593–604. https://doi.org/10.1007/s00441-015-2120-0.
Nelson, Bryn, and William Faquin. 2025. “Amid a Boom in Organ Donation, a Heightened Focus on Cancer Risk in Transplant Recipients: Immunosuppression, Transmissible Infections and Tumors, and Improved Long‐Term Survival Among Organ Recipients Are Requiring More Vigilance for Skin Cancers and Other Malignancies.” Cancer Cytopathology 133 (2): e22932. https://doi.org/10.1002/cncy.22932.
'For the first time, I can also conclude that if you have cancer, elimination of seed-oil consumption should be a first-order alteration to diet, as the potential increase of killer T cells could help fight the disease.'
I'd stopped using seed oil many years ago (thanks to Hyperlipid and commenters like Tucker), but nevertheless had a breast cancer blip six years ago. Somehow I was already aware of the suspected tumerogenicity of O6, so one of my first things actions was to stop eating chicken and pork in addition to avoiding seed oil. Knock on wood, OK so far.
I suppose it was linoleic acid eatin' those two guys