Sunday, November 30, 2025

Metabolic regulation of T-cell function via the urea cycle and nitrogen metabolism

Immunology Metabolism

Fuel vs. Waste: The Metabolic Tug-of-War in Cancer Immunotherapy

How balancing the Nitrogen Cycle can re-awaken the immune system.

Why does immunotherapy cure some patients while failing others? The answer often lies not in the genetics of the cancer cells, but in the chemical "weather" surrounding them; the Tumor Microenvironment (TME).

Two recent studies—one focusing on lung cancer and the other on colorectal cancer—have converged on a single, critical biological mechanism: Nitrogen Metabolism. When read together, they tell a compelling story about how cancer manipulates the Urea Cycle to starve and poison our immune cells.

            Main finding: T-cells (the immune system's soldiers) require a delicate metabolic balance. They need nutrients like Arginine to fight, but they are easily exhausted by metabolic waste like Ammonia. Tumors exploit this by creating an environment that is high in waste and low in fuel.
        

The Mechanism: Two Sides of the Same Coin

Disrupted Urea Cycle

To understand the overlap between these studies, we have to look at the Urea Cycle. This biological pathway is responsible for clearing toxic ammonia and producing Citrulline and Arginine. The studies essentially investigate the two opposing ends of this cycle.

The Problem: Ammonia Toxicity

Based on Bell et al. 2022 Dec (Colorectal Cancer)

In colorectal tumors, the enzyme OTC (Ornithine Transcarbamylase) is often downregulated. This creates a bottleneck in the cycle.

Result: Toxic Ammonia accumulates in the microenvironment.
Effect: High ammonia induces T-cell metabolic reprogramming, forcing them into a state of "exhaustion" (high PD-1 expression).

The Solution: Nutrient Restoration

Based on Miyamoto et al. 2025 Jul (NSCLC)

Since the cycle is broken, T-cells are starved of downstream products. This study supplemented Arginine & Citrulline.

Result: Bypassing the metabolic block ensures T-cells have the fuel they need.
Effect: Supplementation increased the infiltration of CD8+ T-cells and enhanced their killing power.
Note: Only citrulline was able to sustain arginine levels, whereas arginine alone would fail.

Why This Matters for Immunotherapy

Both papers confirm that metabolic intervention is the key to unlocking the potential of checkpoint inhibitors (like anti-PD-1/PD-L1).

When T-cells are drowning in ammonia (Study 2) or starved of arginine (Study 1), they express high levels of PD-1—the "brakes" of the immune system. Simply adding an anti-PD-1 drug isn't enough if the metabolic engine is broken.

By either clearing the ammonia or supplementing the missing nutrients, or both, we can "revive" these exhausted T-cells. This restores sensitivity to immunotherapy by modulating the tumor microenvironment from an immunosuppressive state to an immunostimulatory phenotype, facilitating tumor elimination.

Allicin vs. DFMO (ODC Inhibition)

	DFMO (Standard Drug)	Stabilized Allicin
Mechanism	Binds to the active site.	Thiol Reagent. S-thioallylates cysteine residues on the enzyme surface.
Potency (IC50)	~250 μM (Requires high doses)	~11 nM (Nanomolar potency—23,000x stronger in vitro).
Reversibility	Not Reversible	Reversible (can be titrated out by cellular thiols like glutathione).

Note: Allicin acts as both a STAT3 Inhibitor (anti-stemness) and an ODC Inhibitor (anti-growth).

* Approximately 60-80% of patients do not respond to immunotherapy.

Friday, November 28, 2025

100+ Natural Anti-Cancer Substances

Database of Natural Compounds. This selection includes more than 100 natural substances that have shown promise in cancer research studies. Click on any supplement to explore its mechanisms, research findings, and therapeutic value.

Bovine Tracheal Cartilage

Hericium Erinaceus Extract

Natural Products & Repurposed Drugs: A Visual Guide to Synergy

Natural supplements can be a helpful addition to cancer therapy. For example, they can act as supportive agents that make tumor cells more sensitive to chemotherapy drug, a process known as chemosensitization. Integrating therapies through a scientific approach may lead to substantially improved results. I’ve created a visual guide highlighting synergistic interactions, key pathways, and processes between various compounds. These represent some of the most effective natural substances and repurposed drugs that impair cancer growth and metastatic potential through multiple mechanisms. However, while many compounds demonstrate potent anti-cancer effects in laboratory settings or animal models, they often prove ineffective due to poor bioavailability, unreliable because of hormesis, or even unsafe because of the difficulty in dosing. Understanding these hurdles is key to evaluating complementary treatments. Synergistic combinations could potentially overcome these limitations. This is the core focus of this blog. That said, a critical point to highlight is that supplements, herbs, and repurposed drugs can interfere with cancer treatments. Always consult your healthcare provider or oncologist before taking supplements, as they can interfere with treatment efficacy, increase bleeding, or cause immune impairment from high doses, and therefore should be avoided during active cancer treatment, unless otherwise directed by a licensed medical professional. Refer to the 'Safe Use' page for more critical safety information.

Artemisinin 🛈 ⓟ🟥CT FER ST3 HIF → ↓ DHA docosahexaenoic acid 🛈 ST3 FER

→ Citric acid 🛈 Gi RL RA → Melatonin 🛈 E⏷ ↘ → Shikonin 🛈 Ⓟ → Myricetin 🛈 Ⓟ
→ Honokiol 🛈 LDHAi RMDR → Orlistat 🟪 FAS FER → EGCg 🛈 FAS AA → IP6 *🛈🟩

→ ld Metformin 🟪 → ↓ Shikonin 🛈 → Luteolin ↑ 🛈 FER ↗ → ↖ Curcumin 🛈

→ md Ivermectin 🟪 β-CAT ↑
→ ↓ Diclofenac 🟪 Ⓟ MCT1/4 → D-limonene 🛈 p53 Bcl2
→ ↓ Caffeine → Piperlongumine 🛈 ↓
→ Curcumin → Andrographis 🛈 → Melatonin ↓
→ Apigenin 🛈 → Curcumin 🛈 → Thymoquinone 🛈 AA HIF
→ Baicalein 🛈 HIF AA ST3 hsp90 → Silibinin 🛈 ↑ Jak2 β-CAT

→ Oroxylin-A Gi → Chrysin 🛈 ↑ HK2
→ γ-Tocotrienol HIF ST3

→ Aspirin 🟪 Bcl2 FAS ↑→Vitamin D 🛈 → Lactoferrin RA
→ Phenylbutyrate ↓ 🟪 Ⓟ ↑ ⚪ RA HDACi

→ Mebendazole 🟪 → Melatonin 🛈 E⏷
→ Modified Citrus Pectin 🛈 G3 → Ursolic acid 🛈 FAS E⏷→ Luteolin ↓ ST3

→ Magnolol 🛈 β-CAT + Ai 🛈 ↗ Piperine ↑10x → Curcumin↑→ I3C 🛈 * E⏷

→ Baicalin 🛈 Bcl2 VEGF → EGCg 🛈 ↗

→ ↓ Curcumin 🛈 ↓ RMDR → Luteolin 🛈 TGF-β → Silibinin 🛈

→ Butyrate 🛈 CT → DHA ↓ docosahexaenoic acid 🛈

→ Aspirin 🟪 PDK

→ Piperlongumine 🛈 CT FER ST3 → Sanguinarine 🛈 → Berberine 🛈 → Caffeine

→ Shikonin 🛈 Ⓟ

→ Allicin 🛈 FER RMDR → Ginger/6-Shogaol 🛈 ICD NO▼ → Anthocyanin 🛈 AM▼

→ Bicarbonate 🛈 → Gallic acid 🛈 LDHAi → Shikonin 🛈

+ HDACi 🛈 → Melatonin 🛈 → Curcumin ↓ → Cannabidiol 🛈 → Magnolol

+ aPD(L)1 🛈 Ellagic acid 🛈 ↑ → Quercetin * 🛈 → Luteolin 🛈 FER

→ AHCC 🛈 MiR → Fucoidan 🛈 ST3 HIF FER RA → Resveratrol 🛈 nrf2▲!

→ Silibinin 🛈

→ Rosmarinic acid 🛈
→ Ivermectin 🟪 P-gp β-CAT
→ Ursolic acid 🛈 FAS E⏷
→ 1:2 Resveratrol 🛈 nrf2▲!
→ ↓ Apigenin 🛈 CCAA ↓ → Salvia miltiorrhiza 🛈 FER → ↓ Astragalus 🛈 T ˃

Curcumin 🛈 ST3 G3 MT → Emodin → Celecoxib 🟪 COX-2 → Luteolin 🛈 → Apigenin 🛈

→ 2:3 Docosahexaenoic acid 🛈 → Butyrate 🛈 → Citric acid🛈 Gi RL RA → Graviola 🛈

→ Melatonin → Andrographis 🛈

Danshen ↑ AM▼ 🛈 → Naringin 🛈 RA ↘ → 3:2 Quercetin

→ Shikonin ICD GI E⏷NK→ Apigenin ↑ Fisetin 🛈 ↑→ Aspirin 🟪 PDK

→ Gallic acid 🛈 FER → Chlorogenic acid 🛈
→ Taurine RA ↓
⇒ EGCg ↓ +24h ♻ 🛈 FAS Bcl2 → Quercetin → Grapeseed extract 🛈 AA E⏷ → P. linteus

→ ↓ Honokiol 🛈 CSC
→ Baicalin 🛈 → Magnolol 🛈 Ⓟ
→ ↓ Luteolin 🛈 nrf2▼ TGFβi → Celecoxib 🟪 nrf2▲ → Berbamine 🛈 ST3

→ Curcumin ↑ → Chrysin HIF → Silibinin 🛈

→ IP6 & Inositol 🛈
→ Ginger / 6-Shogaol 🛈 AM▼ → Licorice → Boswellia CCAA Ⓟ
→ Chlorogenic acid 🛈 RAS → Theobromine 🛈 Ⓟ AA E⏷

→ Cinnamon RA

→↓ Thymoquinone 🛈 AA HIF NFi
→↓ Silibinin 🛈 → Baicalein 🛈 HIF AA ST3 → Salvia miltiorrhiza 🛈 AM▼

→ Nigella Sativa ↓ ↓ Thymoquinone 🛈 AA HIF NFi → Emodin

→ Piperine
→ Carvacrol

→ Melatonin 🛈 ℹ HIF SERM NK → Fisetin 🛈 EGFR

→ Ascorbyl Palmitate 🛈
→ Vitamin D 🛈

→ Vitamin C 🛈 HIF LDHAi → Vitamin K2 🛈 E⏷* ↑

→ Bicarbonate 🛈 LDHAi
→ Magnesium RL
→ Juglone CCAA → Selenium (selenite)
→ Vitamin K3
→ Quercetin 🛈 → Piperlongumine

→ Thymoquinone Bcl2/BAX

→ Ashwagandha/Withaferin A 🛈 → CAPE/Propolis 🛈

→ ↓ Vitamin D 🛈 → Lactoferrin RA → Linolenic acid 🛈

⇒+72h Artemisinin ⓟ → -1h Ivermectin 🟪 P-gp

→ Aspirin 🟪 PDK → Ferulic acid 🛈
→ Lycopene 🛈 AI FAK → Capsaicin
→ γ-Tocotrienol

→ Sulforaphane 🛈 HIF ST5 nrf2▲! ↑ → Dihydrocaffeic Acid

→ Ashwagandha 🛈 → PEITC 🛈
→ Aspirin → Methylsulfonylmethane 🛈
→ Biochanin A 🛈
→ Myricetin → Baicalein 🛈

→ Galangal → Tulsi → Piper nigrum

→ ↓ Berberine 🛈 MT CT HIF RMDR → Zinc

→ Oligomeric proanthocyanidins
→ Garcinol 🛈
→ Lactoferrin
→ Carnosic acid↓ → Fisetin 🛈 → Quercetin → Caffeic acid → Coumaric acid 🛈

Mistletoe AA → Chaga 🛈 → Rosmarinic acid 🛈 RMDR EGFR → Cinnamon RA → Berberine

Explanation of symbols & colors

Top 10 natural substances (refer to spreadsheet); yellow colored

→ anticancer synergy with Artemisinin

→ ↑ ↘ ↗ additive or synergistic anticancer effect (at a minimum, evidence from preclinical studies) ⇒ sequential

→ ferroptosis

→ combination may offer hepatoprotective effects

→ likely to be a good anticancer combination (mechanistically, or closely related to similar synergies)

→ offset IL-8 upregulation

🟥 ROS Classification of Natural Compounds in Cancer Therapy

🟪 I've included a few non-oncology drugs that could enhance their anti-cancer action if combined with specific supplements. Repurposing non-oncology drugs is a promising approach to enhancing cancer therapy.

Ⓟ Link to blog or forum post

🛈 Information about the substance

ld: Low dose. md: Moderate Dose

See Key Pathways and Processes below

Enhancing Absorption and Bioavailability

Consuming fat-soluble supplements alongside dietary fats, such as ghee or coconut oil, can enhance their absorption and utilization in the body. The ideal dosage for the compounds discussed in this blog is uncertain and would vary based on the type of cancer, the specific target, and the individual patient's response to the treatment.

Timing: Optimizing Supplement Intake for Enhanced Efficacy

It might be beneficial to take anticancer supplements late at night and to include a time during the night in your supplementation schedule, e.g., 3AM "study suggests that nighttime is the right time for cancer to grow and spread in the body and that administering certain treatments in time with the body's day-night cycle could boost their efficiency" {ref|ref}.

Synergistic Combinations

A natural substance may show potential against cancer. Still, its effectiveness is often limited by the need for excessively high concentrations to achieve significant benefits (in vitro concentrations not achievable in vivo). However, if synergies exist, those same substances may become significantly more effective at lower concentrations. Such combinations of nutraceuticals can also be used to overcome drug resistance or to sensitize cancer cells to therapeutic agents. While some combinations work through additive rather than truly synergistic mechanisms, they deliver meaningful therapeutic benefits through multi-pathway targeting.

Citric acid-mediated ferroptosis strategy

Click to expand the diagram

For more information on this ferroptosis model, please refer to the forum post.

Key Pathways and Processes

Code	Description	Code	Description
ICD	Immunogenic cell death	ST3	STAT3 inhibition
Gi	Inhibitor of glycolysis	ST5	STAT5 inhibition
CT	Cytotoxic	PDK	PDK inhibition
RMDR	Reversing/sensitizing multidrug resistance	RA	Reduces ammonia
MT	Multiple targets	HDACi	HDAC inhibition
CCAA	Cell cycle arrest and apoptosis	MiR	Modulate immune response
FAS	Fatty acid synthase inhibition	E⏷	Reduces estrogen
AA	Anti-angiogenic	RAS	Reducing Ras activity
EGFR	Epidermal growth factor receptor Inhibition	TGFβi	Inhibition of TGF-β
LR	Lactate reduction	LDHAi	Inhibition of LDHA
FER	Ferroptosis induction, avoid co-administration of FER inhibitors: Vitamin K, and other substances. * don't use in a ferroptosis strategy	NK	Stimulates the production of NK cells
AMPK	AMPK activator	G3	Galectin 3 inhibition: MCP, curcumin, spiraeoside (red onions), QiShenYiQi, formic acid (apples, strawberries, raspberries, honey, nettles)
COX-2	COX-2 inhibitor	T	Activation of T cells
AI	Anti-inflammatory	β-CAT	Inhibition of β-catenin protein
FAK	Focal adhesion kinase downregulation	hsp90	Inhibition of HSP90
SERM	Selective estrogen receptor modulator	Jak2	JAK2 inhibition
HIF	Hypoxia-inducible factor inhibition drug resistance▼	nrf2	Nuclear factor-erythroid 2-related factor. The transcription factor NRF2 exhibits a dual role in cancer. Its impact can vary depending on conditions such as cancer stage, cancer type, mutations, and cancer therapy.
AM ▼▲	Autophagy modulation	E!	Caution in hormonal cancers
NO▼	Nitric Oxide	EMT	Epithelial-Mesenchymal Transition Inhibition
ROSI	Reduces oxidative stress and inflammation	TGF-β	TGF-β inhibition
NFi	NF-κβ inhibition	TMA	Target the metabolic adaptability of cancer cells

⚠️Safe and responsible use of natural supplements and repurposed medications

Supplements should only be taken under the supervision of your healthcare provider or oncologist. Supplements or herbal preparations shouldn't be combined with chemotherapy, radiotherapy, immunotherapy, or any other cancer treatment unless the safety and efficacy of such combinations are established. It's vital to ensure that any additions to the standard treatment further improve its effectiveness.

Drug interactions

Always verify potential interactions between your supplements and any medications you are taking. Be aware of how different nutrients interact with each other. Some supplements enhance the absorption of other nutrients, while others may compete. Supplements, herbs, and repurposed drugs can interfere with cancer treatments. Supplements may reduce treatment efficacy, increase bleeding, or cause immune impairment from high doses, and should be avoided during active cancer treatment unless recommended by a doctor.

For informational and research purposes only, none of my writing should be considered medical advice.

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