Core Framework & Diagram What Is Immunometabolism?
July 23, 20261 Min Read What Is Immune Engineering?
July 23, 2026Your immune cells aren't just 'fighters' — they're sophisticated metabolic machines in their own right
—— Immunometabolism: a new field that has redrawn the border between immunology and metabolic medicine.
I. The Warburg Effect: cancer cells and activated immune cells use the same strategy
In 1924, German biochemist Otto Warburg discovered that cancer cells, even in oxygen-rich conditions, prefer glycolysis (rather than the more efficient oxidative phosphorylation) to generate energy — this seemingly 'inefficient' choice he named 'aerobic glycolysis,' later called the 'Warburg Effect.' At the time, nobody understood why cancer cells would do this. Decades later, immunometabolism research gave an unexpected answer: activated immune cells (especially effector T cells and M1 macrophages), in the initial stages of activation, also switch to aerobic glycolysis mode.
Why? Because glycolysis, though inefficient in energy output (only 2 ATP per glucose molecule, versus ~30 from oxidative phosphorylation), generates energy extremely fast, and produces intermediate metabolites (citrate, acetyl-CoA) that can be directly used for nucleotide synthesis, fatty acid synthesis, and amino acid synthesis needed for rapid proliferation. Rapid proliferation is an activated immune cell's most urgent need. This understanding explains why diabetic patients (whose insulin resistance impairs glycolytic efficiency) develop more severe infections — when immune cells cannot efficiently switch to glycolysis mode, their rapid proliferation and cytokine secretion capacity is discounted, and initial infection control is slower.
|
The Warburg Effect isn't cancer cells' 'quirk' — it's the shared strategy of all cells needing rapid proliferation. Activated immune cells and cancer cells are classmates in this respect — this insight fundamentally changed our understanding of metabolism's relationship to immunity. |
2. Succinate: from Krebs cycle metabolite to inflammatory signaling molecule
One of immunometabolism's most surprising discoveries is that metabolites themselves can function as immune signaling molecules — not just energy byproducts, but molecules directly regulating immune gene expression. Succinate is an intermediate metabolite of the Krebs cycle (the core mitochondrial energy production pathway). In 2013, Evanna Mills and Luke O'Neill's research team discovered that after M1 macrophage activation, the Krebs cycle 'breaks' at certain nodes, causing succinate to massively accumulate inside cells. It drives large amounts of IL-1β secretion through two mechanisms: inhibiting HIF-1α's degradation enzyme (prolyl hydroxylase), stabilizing HIF-1α protein and transcriptionally activating IL-1β and other pro-inflammatory genes; and reverse electron transfer (RET) promoting mitochondrial production of large amounts of reactive oxygen species (ROS), which as second messengers activate the inflammasome (NLRP3).
This finding says: IL-1β, this key pro-inflammatory factor, its production amount is directly controlled by intracellular succinate concentration — and succinate concentration is determined by the cell's metabolic state. Looked at conversely: changing the cell's metabolic state (such as by inhibiting specific metabolic enzymes) can directly reduce IL-1β production — a completely new target logic for anti-inflammatory treatment. Similarly, citrate accumulation relates to M1 macrophage fatty acid synthesis and inflammatory mediator (prostaglandin) production; NAD+/NADH ratio affects T cell function and differentiation; glutamine availability affects Th1 vs. Th2 differentiation direction. Metabolites have become immune cell fate regulators.
3. The metabolic war in the tumor microenvironment
Among all application scenarios of immunometabolism, the metabolic competition occurring in the tumor microenvironment (TME) has the most clinical significance. Tumor cells massively consume glucose (Warburg Effect), producing large amounts of lactate, creating the TME's special metabolic state of low glucose, high lactate, low pH. This metabolic state is catastrophic for immune cells: low glucose — tumor-specific T cells and NK cells can't find enough glucose inside the tumor, unable to efficiently switch to glycolysis mode, proliferation and effector function impaired; high lactate — lactate directly inhibits T cell and NK cell cytotoxic activity, while promoting Treg cell function; low pH — acidic environments inhibit NK cell degranulation and T cell cytokine secretion.
Worse still: tumor cells, through competing for arginine (an important amino acid for T cell activation), and secreting adenosine (through CD73/CD39 pathways, suppressing T cell and NK cell A2AR receptors), actively suppress immune cell function at the metabolic level. This is why, even with sufficient immune checkpoint inhibitors removing PD-1/PD-L1 blockade, some patients' tumors still don't respond — because even if T cells are 'thawed,' in metabolically resource-depleted TME, they still cannot work efficiently. Next-generation strategies to address this include: enhancing T cell and NK cell metabolic adaptability in low-glucose, high-lactate environments (through genetic engineering of metabolic genes); targeting tumor glycolysis; and using adenosine pathway inhibitors to improve TME's metabolic immunosuppression.
4. Trained immunity: innate immunity also has 'metabolic memory'
Immunometabolism's other important frontier is the metabolic basis of 'Trained Immunity' concept. Traditional immunology held that only adaptive immunity (T cells, B cells) can form immune memory; innate immunity (NK cells, macrophages, monocytes) doesn't form memory, each response 'starting from scratch.' This understanding was completely changed in 2011 by Mihai Netea and colleagues. They found that monocytes (macrophage precursors), after contact with specific pathogens or stimuli (like BCG vaccine, β-glucan), undergo persistent epigenetic changes — histone methylation and acetylation status changes, putting pro-inflammatory genes in a more 'open' transcriptional state, allowing these cells to produce stronger non-specific responses even when later encountering completely different pathogens. This is called 'Trained Immunity.'
Trained immunity's metabolic basis is also a core finding in immunometabolism research: establishing trained immunity requires metabolic reprogramming — especially specific Krebs cycle changes (accumulated succinate and fumarate as epigenetic regulatory signals) driving histone modification changes. In other words, metabolite changes are the physical write mechanism of innate immune memory. This explains why BCG vaccine (BCG) has broad-spectrum non-specific protective effects (not just against tuberculosis, but against multiple infections), and provides a theoretical basis for next-generation 'broad-spectrum immune enhancement' strategies.
5. Diet directly reprograms immune cells: food is metabolic signal for immunity
The immunometabolism framework provides precise molecular explanations for 'how what you eat affects immunity' — no longer the vague 'eat more vegetables to boost immunity,' but specific: particular food components, by affecting immune cell metabolic programs, change their functional orientation. ω-3 fatty acids (EPA/DHA): integrated into cell membranes, changing immune cell membrane lipid composition, affecting signal receptor clustering and signal transduction efficiency; simultaneously as 'resolvin' precursors, driving M1→M2 polarization transition (from pro-inflammatory to anti-inflammatory repair). Glutamine: is the most important energy substrate and nucleotide synthesis raw material for T cell and NK cell activation; insufficient glutamine supply directly limits the scale of immune cell activation. Arginine: is the direct precursor for NO synthesis, and NO is NK cells' and M1 macrophages' anti-pathogen and anti-tumor weapon; the tumor microenvironment suppresses NK cells through arginine competition. β-hydroxybutyrate (BHB, ketone body): ketone bodies produced by fasting and ketogenic diets can directly inhibit NLRP3 inflammasome, reducing IL-1β and IL-18 secretion, with systemic anti-inflammatory effects. Short-chain fatty acids (SCFAs, especially butyrate): produced by gut microbiome fermenting fiber, changing immune cell gene expression through HDAC inhibition, promoting Treg cell development, maintaining immune tolerance.
6. Antibiotics: use when necessary, but be clear about the cost
Antibiotics have saved countless lives — this is completely uncontested. But their impact on gut microbiome deserves serious attention. A single course of broad-spectrum antibiotics can eliminate thirty to fifty percent of gut bacterial species within days. Microbiome recovery usually takes weeks to months, and some research shows that in certain cases, microbiome diversity has still not fully recovered to pre-use levels after a year. This doesn't mean antibiotics shouldn't be used. Infections need treatment. But in unnecessary situations (like demanding antibiotics for viral colds), the cost is real — you're paying the price of declining gut immune function for a treatment without actual meaning. After antibiotic courses, increasing fermented food and dietary fiber intake helps accelerate microbiome recovery.
|
Gut microbiome can be rapidly affected by diet. 3 days of high-fiber + fermented foods can begin changing microbiome composition. The window is always open — no need to wait until 'prepared.' |
Frequently Asked Questions