Table 4.

Overview of micronutrients and their cancer-specific effects, highlighting the mechanisms of action, impact on various cancer types, and key research findings.

Micronutrient	Cancer Types Addressed	Mechanism of Action	Specific Impact on Cancer	Ref
Vitamin A	Lung	Antiproliferative Effect: Vitamin A and its derivatives have antiproliferative effects via growth arrest signaling, promotion of differentiation, and induction of apoptosis. These effects are primarily mediated through retinoid receptors (RAR and RXR) that function as transcription factors modulating gene expression.	Limited Clinical Evidence: While preclinical studies have shown positive effects, clinical evidence for Vitamin A in preventing or treating lung cancer is limited. Some RCTs found no significant effect, whereas the CARET trial even found increased risk of lung cancer with the use of Vitamin A and beta-carotene in smokers.	[82]
		Suppression of Proliferative Markers: Retinoic acid downregulates markers such as hTERT, cyclins D1 and 3, and growth factors like EGFR and VEGF, inhibiting tumor growth, angiogenesis, and metastasis.	Event-Free Survival: In some studies, Vitamin A was associated with a small improvement in event-free survival (RR 1.24), suggesting a possible benefit in reducing progression.
		Retinoid Receptors: Vitamin A exerts its effects through retinoic acid receptors (RAR and RXR), leading to G1 cell cycle arrest and modulation of key signaling pathways involved in cancer progression.	Synthetic Derivatives: The synthetic rexinoid bexarotene showed promising results in improving survival in a subset of patients, indicating potential for targeted use of Vitamin A derivatives.
	Leukemia	Induces Differentiation: ATRA induces differentiation of promyelocytic leukemia cells by dissociating the histone deacetylase complex from the PML-RARα fusion protein, promoting coactivator binding and transcription.	Improved Survival: ATRA, combined with chemotherapy, significantly improved 5-year overall survival (OS: 87 %) and event-free survival (EFS: 76 %) compared to conventional therapy.	[83]
		Reduces Coagulation Activity: ATRA downregulates procoagulant activity in promyelocytic blasts, reducing the risk of fatal bleeding events.	Reduced Early Deaths: Use of ATRA reduced early deaths from severe bleeding and sepsis, showing significant improvement in patient outcomes.
		Enhances Immune Function: Increases maturation of neutrophils, leading to enhanced immunological function and reduced infection risk.	Manageable Side Effects: Common side effects included headaches, fever, and retinoic acid syndrome, which were manageable with dose adjustment and supportive treatment.
	Malignant Melanoma	Inhibition of Growth and Proliferation: ATRA binds to retinoic acid receptors (RAR) in cancer cells, inhibiting growth, proliferation, and promoting differentiation.	Reduced Cell Proliferation: The combination of ATRA and DBZ significantly reduces melanoma cell proliferation compared to individual treatments. Increased Apoptosis: ATRA promotes apoptosis, contributing to the suppression of melanoma cells. Inhibition of Cell Migration: The combination treatment notably decreases cell migration, reducing the potential for metastasis.	[84]
		Synergistic Action with Dacarbazine: The combination of ATRA and dacarbazine (DBZ) enhances anticancer efficacy through apoptosis induction, cell cycle arrest, and inhibition of migration.
Vitamin C	Breast Cancer	Pro-apoptotic Effect: High-dose Vitamin C induces apoptosis in breast cancer cells by increasing reactive oxygen species (ROS), leading to DNA damage and cell death.	Reduced Proliferation: High-dose Vitamin C significantly reduces the proliferation of breast cancer cell lines (e.g., MDA-MB-231, MCF-7, and SK-BR3) without affecting normal cells. Enhanced Effect with Anti-cancer Agents: Combining high-dose Vitamin C with chemotherapy agents (e.g., tamoxifen, eribulin mesylate, trastuzumab) further inhibits breast cancer cell growth compared to using the chemotherapy agent alone. Effectiveness on Drug-resistant Cells: High-dose Vitamin C inhibits growth in chemotherapy-resistant breast cancer cells, suggesting a role in overcoming resistance.	[85]
		Reduced Catalase Activity: Cancer cells, such as MDA-MB-231 and MCF-7, have lower catalase activity compared to normal cells, allowing ROS accumulation and enhanced pro-oxidant activity of Vitamin C.
	Gastric Cancer	Antioxidant and Inhibition of Carcinogenic Compounds: Vitamin C acts as an antioxidant and inhibits the formation of carcinogenic N-nitroso compounds in the stomach.	Inverse Association with Plasma Vitamin C: High plasma Vitamin C levels were associated with a reduced risk of gastric cancer (OR = 0.55 for the highest vs. lowest quartile).	[86]
		Quenching Reactive Oxygen Species (ROS): Vitamin C scavenges reactive oxygen species produced in the gastric environment, limiting oxidative damage in gastric epithelial cells.	Effect Modulation by Diet: The inverse association between plasma Vitamin C levels and gastric cancer risk was more pronounced in individuals with higher consumption of red and processed meats.
	Colorectal Cancer (CRC)	Induces Apoptosis: High-dose Vitamin C induces apoptosis in CRC cells, particularly those with high MALAT1 expression, by increasing reactive oxygen species (ROS) and oxidative stress.	Suppression of Tumor Growth: High-dose Vitamin C suppresses CRC growth in both xenograft and peritoneal implantation metastasis models.	[87]
		Cell Cycle Arrest: Vitamin C leads to S-phase arrest, reducing the proliferation of cancer cells.	Inhibition of Metastasis: High-dose Vitamin C significantly reduces metastasis in mouse models, suggesting its role in limiting cancer spread.
		Reduction of MALAT1 Expression: High-dose Vitamin C reduces MALAT1 expression, which is associated with increased CRC progression, thereby inhibiting tumor growth.	Enhanced Sensitivity in High MALAT1 Cells: CRC cells with higher MALAT1 expression are more susceptible to Vitamin C treatment, indicating a targeted effect based on genetic expression profiles.
	Colorectal Cancer	Selective Uptake via GLUT1: Vitamin C (in its oxidized form, dehydroascorbate or DHA) is selectively taken up by KRAS and BRAF mutant CRC cells via the GLUT1 transporter.	Selective Cytotoxicity: High-dose Vitamin C selectively kills KRAS and BRAF mutant CRC cells by exploiting their glycolytic dependency, resulting in reduced tumor growth in both in vitro and in vivo models.	[88]
		Oxidative Stress and GAPDH Inhibition: The uptake of DHA causes oxidative stress, depletes glutathione (GSH), and inactivates glyceraldehyde 3-phosphate dehydrogenase (GAPDH), leading to an energetic crisis and cell death in glycolysis-dependent cancer cells.	Inhibition of Tumor Growth: High-dose Vitamin C significantly reduces tumor growth in KRAS and BRAF mutant xenograft models, indicating its potential therapeutic effect against these types of mutations.
Vitamin D	Colorectal Cancer	Cell Differentiation and Immune Modulation: Vitamin D, in the form of calcitriol, binds to vitamin D receptors (VDR), promoting cellular differentiation and modulating the immune response.	Reduced Cancer Incidence: Epidemiological evidence suggests an inverse association between high plasma levels of Vitamin D (25(OH)D) and reduced risk of CRC.	[89]
		Inhibition of Proliferation and Induction of Apoptosis: Calcitriol inhibits cancer cell proliferation by inducing G1 phase cell cycle arrest via upregulation of CDK inhibitors (e.g., p21, p27) and promoting apoptosis through upregulation of pro-apoptotic proteins (e.g., BAK1, BAX).	Tumor Growth Inhibition: Calcitriol treatment has shown to inhibit tumor growth in colorectal cancer models by targeting multiple pathways, including WNT signaling and CTNNB1 activity.
		Anti-Angiogenesis: Calcitriol inhibits angiogenesis by reducing VEGF expression and endothelial cell proliferation.	Immune System Modulation: Vitamin D enhances immune cell function, which is associated with a reduction in CRC risk, particularly in tumors with high immune infiltration.
	Breast Cancer	Growth Arrest and Apoptosis: 1,25(OH)2D induces cell cycle arrest by upregulating cyclin-dependent kinase inhibitors (e.g., p21, p27) and promoting apoptosis through downregulation of anti-apoptotic proteins (e.g., Bcl-2, Bcl-XL) and upregulation of pro-apoptotic proteins (e.g., Bax, Bak).	Reduced Breast Cancer Risk: Epidemiological studies suggest an inverse association between serum 25(OH)D levels and breast cancer risk, with higher levels correlating with reduced risk.	[90]
		Inhibition of Invasion and Metastasis: 1,25(OH)2D increases E-cadherin expression, inhibits matrix metalloproteinases (MMPs), and suppresses angiogenesis, reducing the ability of breast cancer cells to invade and metastasize.	Lower Cancer Recurrence and Mortality: Higher levels of Vitamin D are associated with reduced risk of breast cancer recurrence and mortality in women with early-stage breast cancer.
		Estrogen Pathway Inhibition: 1,25(OH)2D suppresses the synthesis and biological action of estrogens by downregulating aromatase enzyme and estrogen receptor (ER) expression, thereby reducing estrogen-driven breast cancer cell proliferation.	Improved Prognosis: Sufficient Vitamin D levels (>30 ng/mL) are linked to improved prognosis and survival rates in breast cancer patients.
	Prostate Cancer	Inhibition of EMT: Calcitriol (active Vitamin D) inhibits epithelial-mesenchymal transition (EMT) by downregulating EMT-related genes (e.g., Zeb1, Snail) and reducing the interaction between β-catenin and TCF4, which are crucial for prostate cancer cell invasion and metastasis.	Reduced Growth and Metastasis: Vitamin D deficiency was found to aggravate prostate cancer growth and metastasis, while calcitriol treatment inhibited tumor growth in two prostate cancer mouse models. Inhibition of Invasion and Migration: In prostate cancer cell lines (PC-3 and DU145), calcitriol effectively inhibited cell migration and invasion, contributing to reduced metastatic potential.	[91]
		Promotion of Adherens Junction Formation: Calcitriol promotes the formation of the β-catenin/E-cadherin complex, enhancing cell adhesion and maintaining epithelial integrity, which helps suppress tumor spread.
		Suppression of β-catenin Signaling: Calcitriol reduces β-catenin phosphorylation and decreases its transcriptional activity with TCF4, inhibiting proliferation and migration of prostate cancer cells.
Vitamin E	Liver Cancer	Antioxidant Activity: Vitamin E acts as a potent antioxidant by scavenging reactive oxygen species (ROS) and reducing oxidative stress, which is a major factor in liver carcinogenesis. Chromosomal and Mitochondrial DNA Protection: Vitamin E supplementation enhances chromosomal stability and reduces mitochondrial DNA (mtDNA) damage, which are associated with decreased tumor progression. Suppression of Cell Proliferation and Apoptosis: Vitamin E reduces hepatocyte proliferation and apoptosis by lowering ROS levels and enhancing chromosomal integrity, preventing preneoplastic lesion formation.	Reduced Tumor Incidence: Vitamin E reduced the incidence of liver adenomas by 65 % and prevented the development of carcinomas in a transgenic mouse model overexpressing c-myc and TGFa. Inhibition of Neoplastic Development: The dietary supplementation of Vitamin E significantly reduced tumor growth and size, demonstrating its effectiveness in inhibiting both the initiation and progression of liver cancer.	[92]
	Breast Cancer	Drug Resistance Reversal: Vitamin E conjugate (as part of Chitosan/Vitamin E micelles) enhances the uptake of oxaliplatin and reverses multidrug resistance (MDR) in breast cancer cells.	Decreased IC50 Values: The micelles significantly reduced IC50 values in both ER+/PR+/HER2− and TNBC cell lines, indicating enhanced efficacy compared to free oxaliplatin. Enhanced Apoptosis and DNA Fragmentation: The micelles induced extensive DNA fragmentation, mitochondrial depolarization, and apoptosis, resulting in effective inhibition of breast cancer cell growth. Reduced Tumor Growth and Nephrotoxicity: In vivo studies on 4T1(Luc)-tumor-bearing mice showed significant tumor growth inhibition, prolonged survival, and reduced nephrotoxicity compared to oxaliplatin alone.	[93]
		Mitochondrial Depolarization: Induces mitochondrial depolarization, which leads to apoptosis in breast cancer cells.
		Reactive Oxygen Species (ROS) Generation: Increases ROS levels, which contributes to DNA damage and apoptosis.
		Cell Cycle Arrest: Causes G2/M cell cycle arrest, leading to inhibited cancer cell proliferation.
Selenium	Prostate Cancer	Modulation of Antioxidant Pathways: Selenium has been shown to modulate antioxidant pathways, helping to reduce oxidative stress that can contribute to cancer progression.	Increased Risk with High-Dose Supplementation: Men with nonmetastatic prostate cancer who consumed selenium supplementation of 140 μg/day or more after diagnosis had a 2.60-fold higher risk of prostate cancer mortality compared to nonusers.	[94]
		Influence on Apoptosis and Cellular Proliferation: Selenium impacts apoptosis and inhibits cellular proliferation, which are crucial in cancer prevention and slowing disease progression. However, very high selenium levels may lead to adverse effects, potentially affecting apoptosis and increasing cancer risk.	No Significant Effect on Biochemical Recurrence: Selenium supplementation was not associated with a statistically significant effect on biochemical recurrence of prostate cancer.
		Potential U-Shaped Dose-Response: The study suggests a U-shaped dose-response relationship for selenium, where both deficiency and excess can lead to increased risk, indicating the need for an optimal selenium range for beneficial effects.	Increased Mortality: Selenium supplementation at high doses increased prostate cancer-specific mortality, particularly among individuals with already sufficient selenium levels.
	Lung Cancer	Antioxidant Function: Selenium acts as an antioxidant, supporting selenoproteins that help mitigate oxidative stress, which can contribute to cancer progression.	Improved Overall Survival in Stage I: Higher serum selenium levels (>69 μg/L) at the time of diagnosis were significantly associated with improved overall survival in patients with stage I lung cancer. Patients in the highest tertile of selenium levels had an 80-month survival rate of 79.5 %, compared to 58.1 % in the lowest tertile.	[95]
		Stimulation of Immune Function: Selenium enhances the activity of immune cells, including cytotoxic lymphocytes and natural killer cells, which can target cancer cells.	Reduced Mortality Risk: Patients with higher selenium levels had a reduced risk of death, with a hazard ratio of 2.73 for those in the lowest selenium tertile compared to the highest, indicating the importance of sufficient selenium levels for prognosis in early-stage lung cancer.
	Colorectal Cancer	Antioxidant Defense: Selenium, through its role in selenoproteins like Selenoprotein P (SePP), contributes to reducing oxidative stress, which is a known factor in colorectal cancer development.	Reduced CRC Risk: Higher selenium concentrations are inversely associated with colorectal cancer risk. This association was found to be statistically significant for women, with an Incidence Rate Ratio (IRR) of 0.83 (95 % CI: 0.70–0.97) per 25 μg/L increase in selenium levels. Gender-Specific Findings: The protective effect of selenium was more evident in women compared to men, suggesting a potential role of sex-specific metabolism and response to selenium.	[96]
		Modulation of Inflammatory Response: Selenium is involved in regulating the inflammatory response, which plays a role in colorectal cancer progression.
		Role of Selenoprotein P (SePP): Higher levels of SePP are associated with a decreased risk of colorectal cancer, especially among women. SePP serves as a key transporter of selenium, supporting cellular protection against oxidative damage.
Zinc	Esophageal Squamous Cell Carcinoma (ESCC)	Inflammatory Modulation: Zinc deficiency (ZD) induces a distinct inflammatory gene signature in the esophageal mucosa, upregulating pro-inflammatory mediators such as S100a8, S100a9, and Cox-2, contributing to an environment conducive to cancer development.	Increased Cancer Incidence with Zinc Deficiency: Prolonged ZD in combination with low doses of the carcinogen N-nitrosomethylbenzylamine (NMBA) led to a 66.7 % incidence of ESCC in rats. Zinc sufficiency or replenishment, however, prevented cancer formation. Reduction of Dysplasia and Neoplasia with Zinc Replenishment: Zinc replenishment after carcinogen exposure reversed dysplastic and neoplastic changes, demonstrating zinc's protective role against cancer progression.	[97]
		Suppression of Inflammatory Signature by Zinc Replenishment: Zinc replenishment reverses the inflammatory gene signature, reducing the expression of numerous inflammation-related genes (e.g., CXC and CC chemokines, Cox-2) and preventing the progression from dysplasia to neoplasia.
		Effect on Cell Proliferation: Zinc deficiency leads to increased cellular proliferation and hyperplasia, whereas zinc sufficiency helps maintain cellular homeostasis by preventing excessive cell proliferation.
	Colorectal Cancer (CRC)	Antioxidant Defense Enhancement: Zinc acts as a cofactor for the antioxidant enzyme superoxide dismutase (SOD), which helps neutralize reactive oxygen species (ROS) during chemotherapy.	Increased SOD Activity: Patients who received zinc supplementation showed significantly higher SOD activity during chemotherapy compared to the placebo group, suggesting improved antioxidant defenses.	[80]
		Modulation of Antioxidant Enzymes: Zinc supplementation increased SOD activity during chemotherapy cycles, which plays a critical role in converting superoxide radicals to hydrogen peroxide, thus reducing oxidative stress.	Maintenance of Vitamin E Levels: Zinc supplementation maintained plasma vitamin E levels during chemotherapy, which was not observed in the placebo group. This suggests a protective role of zinc in reducing oxidative damage during cancer treatment.
		Maintenance of Antioxidant Vitamins: Zinc helped maintain plasma vitamin E concentrations, which is crucial for reducing lipid peroxidation during chemotherapy.	No Effect on Lipid Peroxidation Markers: Despite increased SOD activity, zinc supplementation did not significantly affect lipid peroxidation markers (MDA and 8-isoprostane), suggesting that the effect of zinc was primarily on enzymatic antioxidant defense rather than directly reducing lipid oxidation.