Omega-3 Fatty Acids

The Good Fat

The term omega-3 polyunsaturated fatty acids (omega-3 FAs) refers to a group of polyunsaturated fatty acids (PUFA) which contain a double carbon bond at the third carbon atom (n-3 position) from the methyl end of the carbon chain. Alpha-linolenic acid (ALA, 18-carbon PUFA obtained from plant sources), eicosapentanoic (EPA, 20-carbon PUFA from fish) and docosahexaenoic acid (DHA, 22-carbon PUFA obtained from marine source) are the most common omega-3 FAs. (1)

Over the past decades, extensive studies have addressed the therapeutic effects of omega-3 polyunsaturated fatty acids (omega-3 FAs) against different human diseases such as cardiovascular and neurodegenerative diseases and cancer. (1) These studies have demonstrated the clinical utility and safety of these natural occurring substances. Furthermore, more recently, omega-3 FAs have been demonstrated to improve the outcome against certain types of cancer, improve the efficacy and tolerability of chemotherapy and improve quality of life indicators. (1) In addition, omega 3 FA improves cancer cachexia.

Anticancer pathways and mechanisms

Proposed anti‑cancer mechanisms

• Incorporation of eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) into tumor cell membranes can alter signaling pathways that control growth, leading to reduced proliferation and increased sensitivity to growth‑inhibitory signals.(2)​

• Omega‑3s can promote apoptosis (programmed cell death) through caspase activation and mitochondrial pathways, helping trigger death of cancer cells in experimental models.(3)

• They can reduce production of pro‑inflammatory eicosanoids and cytokines (for example TNF‑α, IL‑6), shifting the balance away from chronic inflammation that favors tumor progression.(4)

• Omega‑3s influence angiogenesis and metastasis by modulating factors involved in new blood vessel formation and tissue invasion, potentially limiting tumor spread in preclinical studies.​(2)

• Early work suggests they may interact with immune pathways, and in mouse models, a high omega‑3 diet enhanced the effect of immunotherapy and blocked tumor growth compared with high omega‑6 diets.

The four main antineoplastic activities omega-3 FA include, (i) modulation of cyclooxygenase (COX) activity; (ii) alteration of membrane dynamics and cell surface receptor function, (iii) increased cellular oxidative stress, and iv) the production of novel anti-inflammatory lipid mediators including resolvins, protectins and maresins. (5, 6)

Omega-3 FAs compete with linoleic acids (LA) as a key nutrient in cancer. The ratio of the two classes of FAs is important since omega-3 and omega-6 share the same biochemical pathways and can compete between them to generate imbalances. The precursor of the omega-6 FA, LA, is associated with pro-inflammatory response. Cancer progression seems to be influenced by the ratio omega-3/omega-6 FA in the diet, rather than by their singular intake. (1) While LA promotes the survival of tumor cells preventing their death, omega-3 FAs promote the self-destruction of the tumor cells, thus limiting the expansion of cancer. Omega-3 FAs, especially EPA and DHA, affect cancer cell replication, cell cycle, and cell death. In this context, in vitro and in vivo studies have shown that omega-3 FAs sensitize tumor cells to anticancer drugs. Omega-3 FAs also modulate several pathways including modulating gene expression involved in multiple signaling pathways including NF-κB, Notch, Hedgehog, Wnt, and mitogen-activated protein kinases (MAPKs). (7) Omega-3 FAs suppress the formation of arachidonic acid derived prostanoids (prostaglandin E2), which are responsible for inflammatory response, cell growth, apoptosis, angiogenesis, and metastasis. (8) EPA and DHA induce apoptosis in breast cancer cell lines by activation of Bcl2 expression and pro-caspase 8, together with reduction of EGFR activation. (8) Omega-3 FAs can block the activity of self-renewing colon cancer stem cells (CSC). (9, 10)

Figure 1. Anticancer pathways of Omega-3 Fatty Acids

Omeg-6 fatty acids

Current evidence suggests that diets high in industrial seed oils rich in omega-6 polyunsaturated fatty acids (particularly linoleic acid) may create a biological environment that favors cancer progression, although the strength of the evidence varies by cancer type and is stronger in experimental models than in human clinical studies. Excessive intake of omega-6 fatty acids—especially when accompanied by a low intake of marine omega-3 fatty acids—can increase the production of pro-inflammatory lipid mediators, promote oxidative stress and lipid peroxidation, and alter cell membrane composition, thereby influencing signaling pathways involved in proliferation, angiogenesis, invasion, and immune evasion. Oxidized linoleic acid metabolites (OXLAMs) have been implicated in activating pathways such as NF-κB, PI3K/Akt, and COX-2, while chronic hyperinsulinemia associated with highly processed, seed oil-rich Western diets may further support the Warburg phenotype and metabolic flexibility of cancer cells. Within the Metabolic Trap framework, excessive omega-6 intake may therefore oppose several therapeutic goals by sustaining inflammation (Axis 4), enhancing tumor metabolic adaptation (Axes 1 and 2), and contributing to an immunosuppressive tumor microenvironment (Axis 5). For these reasons, many integrative oncology programs emphasize reducing consumption of ultra-processed foods and industrial seed oils while restoring a healthier omega-6:omega-3 ratio through increased intake of marine omega-3 fatty acids. It is important to note, however, that although mechanistic and observational evidence is substantial, definitive randomized clinical trials demonstrating that reducing seed oil consumption improves cancer outcomes are currently lacking.

Clinical studies

In a prospective RCT, the intake of omega-3 FAs and vitamin D was associated with a dramatic reduction in the risk of developing cancer. (11) In the VITAL cohort study conducted in postmenopausal women, the current use of fish oil was associated with reduced risk of breast cancer (HR 0.68, 95% CI: 0.50-0.92). (12) A meta-analysis of 16 prospective cohort studies examining marine omega-3 FAs intake suggests a reduction in breast cancer risk when individuals with highest intakes are compared with those with lowest intakes of marine PUFA. (13) Two large observational studies have demonstrated significant inverse relationships between omega-3 FAs intake and the risk of colorectal neoplasia. (14, 15)

A recent meta-analysis of six prospective case–control studies and five cohort studies evaluated the omega-3:omega-6 intake ratio and/or omega-3:omega-6 ratio in serum phospholipids in relation to the risk of developing breast cancer. (16) The authors concluded that each 1/10 increment in the dietary n-3:n-6 ratio was associated with a 6% reduction in breast cancer risk, and each 1/10 increment in the serum n-3:n-6 phospholipid ratio was associated with a 27% reduction in breast cancer risk.

Patients with familial adenomatous polyposis who had previously undergone colectomy and ileorectal anastomosis were randomized to 2g EPA/day or placebo. In this RCT there was a 22.4% reduction in polyp number in the EPA group (p=0.01). (17) A phase II study evaluated addition of 1.8 g DHA daily to an anthracycline based chemotherapy regimen for metastatic breast cancer. The DHA group had a significantly longer time to disease progression and overall survival (median 34 months vs 18 months). (18) In a small RCT, supplementation with fish oil increased first line chemotherapy efficacy in patients with advanced non-small cell lung cancer.(19)

Higher intakes of EPA and DHA from dietary sources were reported to be associated with a 25% reduction in breast cancer recurrence and improved overall mortality in a large cohort of over 3,000 women with early-stage breast cancer followed for a median of 7 years. (20) Cohort studies assessing the risk of prostate cancer mortality and fish omega-3 FAs intake suggest an association between higher intake of fish and decreased risk of prostate cancer–related death.(21) In a small RCT, patients with leukemia or lymphoma concurrently receiving chemotherapy were randomized to receive 2g /day of fish oil or placebo for 9 weeks. (22) Overall long-term survival was greater in the fish oil group (p < 0.05). In a meta-analysis which included 12 RCT and 1184 patients with cancer cachexia, the use of omega-3 FAs was associated with a significant improvement in quality of life and duration of survival (median survival ratio, 1.10; 95% CI, 1.02-1.19; P = .014). (23)

Types of cancer that omega-3 fatty acids may be beneficial for

Omega-3 FAs may be beneficial for breast cancer, colorectal cancer, leukemia, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, lung cancer, and head and neck cancer.(1)

Dosing and cautions

We suggest a dose of 2-4 g omega-3 FAs daily. Omega-3 fatty acids may increase the risk of bleeding and should be used cautiously in patients on anticoagulants.

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References

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2. Stephenson JA, Al-Taan O, Arshad A, Morgan B, Metcalfe MS, Dennison AR. The multifaceted effects of omega-3 polyunsaturated Fatty acids on the hallmarks of cancer. J Lipids. 2013;2013:261247.

3. Abbas K, Kamil F, Tanveer Y, Alam M, Zehra Z, Mustafa M. Omega-3 Fatty Acids from Fish: A Novel Approach in Cancer Therapy. Biosciences Biotechnology Research Asia. 2024;21:1303–17.

4. Liu H, Chen J, Shao W, Yan S, Ding S. Efficacy and safety of Omega-3 polyunsaturated fatty acids in adjuvant treatments for colorectal cancer: A meta-analysis of randomized controlled trials. Front Pharmacol. 2023;14:1004465.

5. Cockbain AJ, Toogood GJ, Hull MA. Omega-3 polyunsaturated fatty acids for the treatment and prevention of colorectal cancer. Gut. 2012;61(1):135–49.

6. Fabian CJ, Kimler BF, Hursting SD. Omega-3 fatty acids for breast cancer prevention and survivorship. Breast Cancer Res. 2015;17(1):62.

7. Xue M, Wang Q, Zhao J, Dong L, Ge Y, Hou L, et al. Docosahexaenoic acid inhibited the Wnt/β-catenin pathway and suppressed breast cancer cells in vitro and in vivo. J Nutr Biochem. 2014;25(2):104–10.

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9. Vasudevan A, Yu Y, Banerjee S, Woods J, Farhana L, Rajendra SG, et al. Omega-3 fatty acid is a potential preventive agent for recurrent colon cancer. Cancer Prev Res (Phila). 2014;7(11):1138–48.

10. De Carlo F, Witte TR, Hardman WE, Claudio PP. Omega-3 eicosapentaenoic acid decreases CD133 colon cancer stem-like cell marker expression while increasing sensitivity to chemotherapy. PLoS One. 2013;8(7):e69760.

11. Bischoff-Ferrari HA, Willett WC, Manson JE, Dawson-Hughes B, Manz MG, Theller R, et al. Combined Vitamin D, omega-3 fatty acids, and a simple home exercise program may reduce cancer risk among active adults aged 70 and older: A randomized clinical trial. Front. Aging. 2022;3:852643.

12. Brasky TM, Lampe JW, Potter JD, Patterson RE, White E. Specialty supplements and breast cancer risk in the VITamins And Lifestyle (VITAL) Cohort. Cancer Epidemiol Biomarkers Prev. 2010;19(7):1696–708.

13. Zheng JS, Hu XJ, Zhao YM, Yang J, Li D. Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies. Bmj. 2013;346:f3706.

14. Kim S, Sandler DP, Galanko J, Martin C, Sandler RS. Intake of polyunsaturated fatty acids and distal large bowel cancer risk in whites and African Americans. Am J Epidemiol. 2010;171(9):969–79.

15. Pot GK, Geelen A, van Heijningen EM, Siezen CL, van Kranen HJ, Kampman E. Opposing associations of serum n-3 and n-6 polyunsaturated fatty acids with colorectal adenoma risk: an endoscopy-based case-control study. Int J Cancer. 2008;123(8):1974–7.

16. Yang B, Ren XL, Fu YQ, Gao JL, Li D. Ratio of n-3/n-6 PUFAs and risk of breast cancer: a meta-analysis of 274135 adult females from 11 independent prospective studies. BMC Cancer. 2014;14:105.

17. West NJ, Clark SK, Phillips RK, Hutchinson JM, Leicester RJ, Belluzzi A, et al. Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis. Gut. 2010;59(7):918–25.

18. Bougnoux P, Hajjaji N, Ferrasson MN, Giraudeau B, Couet C, Le Floch O. Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial. Br J Cancer. 2009;101(12):1978–85.

19. Murphy RA, Mourtzakis M, Chu QS, Baracos VE, Reiman T, Mazurak VC. Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer. Cancer. 2011;117(16):3774–80.

20. Patterson RE, Flatt SW, Newman VA, Natarajan L, Rock CL, Thomson CA, et al. Marine fatty acid intake is associated with breast cancer prognosis. J Nutr. 2011;141(2):201–6.

21. Aucoin M, Cooley K, Knee C, Fritz H, Balneaves LG, Breau R, et al. Fish-Derived Omega-3 Fatty Acids and Prostate Cancer: A Systematic Review. Integr Cancer Ther. 2017;16(1):32–62.

22. Chagas TR, Borges DS, de Oliveira PF, Mocellin MC, Barbosa AM, Camargo CQ, et al. Oral fish oil positively influences nutritional-inflammatory risk in patients with haematological malignancies during chemotherapy with an impact on long-term survival: a randomised clinical trial. J Hum Nutr Diet. 2017;30(6):681–92.

23. Jin X, Xu XT, Tian MX, Dai Z. Omega-3 polyunsaterated fatty acids improve quality of life and survival, but not body weight in cancer cachexia: A systematic review and meta-analysis of controlled trials. Nutr Res. 2022;107:165–78.