Historical rise of cancer and dietary linoleic acid: Mechanisms and therapeutic strategies

Table 2 Associations between linoleic acid and cancer risk or progression

Cancer type	Study design	Key findings/interpretation	Ref.
Breast (ER+/ER-)	Mendelian randomization (United Kingdom Biobank)	Genetically elevated plasma LA was associated with increased risk of ER+ breast cancer. This suggests a potential causal relationship, though dietary intake thresholds were not assessed. No control population consuming < 5% LA of total daily energy	[263]
Triple-negative breast cancer	Tumor metabolomics + xenograft	LA served as a key metabolic substrate driving tumor progression via upregulated β-oxidation and PPARα signaling. In vivo, LA supplementation accelerated triple-negative breast cancer tumor growth. Effect not observed under low-LA feeding	[13]
Prostate	Dose-response meta-analysis of prospective cohorts	No consistent association between dietary or biomarker LA and prostate cancer risk. Studies lacked low-LA intake arms (< 5% of daily calories), limiting ability to detect nonlinear effects	[31]
Non-small-cell lung	United Kingdom Biobank (plasma LA)	Higher circulating LA associated with significantly reduced incidence of non-small-cell lung. LA was inversely associated with time to diagnosis and overall risk. Relationship limited to biomarker data; dietary LA thresholds not stratified	[264]
Lung (all histologies)	Prospective cohort (plasma fatty acids)	Circulating LA inversely associated with lung cancer risk across histologic subtypes. No evidence of U-shaped risk or high-LA threshold effects. No low-intake (< 5% energy) group included	[265]
Pancreatic	Case-control (PanC Consortium)	Slight inverse association between LA intake and pancreatic cancer risk. Association was non-linear, with attenuation at higher intakes. No stratification by low-LA consumption	[266]
Colorectal	Meta-analysis of dietary + biomarker studies	Pooled analysis found modestly increased colorectal cancer risk with higher LA intake. Effect stronger for dietary LA vs plasma biomarker. Studies lacked representation of < 5% LA intake groups	[29]
Colorectal (sub-site stratified)	Pooled analysis (54 studies + 4 Mendelian randomization)	Increased risk particularly for rectal cancer. No protective effect observed. Sub-group analysis suggests dose-response relationship, but low-LA intake not studied	[11]
Colon	Animal + human tissue (CYP- epoxyoctadecenoic acids mechanism)	LA-rich diets led to higher levels of pro-inflammatory epoxyoctadecenoic acids via CYP metabolism, promoting colonic tumorigenesis. Effects confirmed in human samples. No low-LA comparator group included	[267]
Colon and rectum	EPIC-InterAct (plasma phospholipid LA)	Plasma LA not significantly associated with colorectal cancer risk. Null finding, but biomarker variability may mask associations. No data on dietary intake below 5% energy from LA	[268]
Kidney	Pan-cancer Mendelian randomization	Genetically predicted higher LA levels associated with increased kidney cancer risk. Suggests possible causal effect. No reference to real-world low-LA cohorts	[269]
Hepatocellular carcinoma	Tumor microenvironment analysis	LA uptake enhanced tumor cell proliferation via upregulation of LINC01116 and fatty acid metabolism genes. Supported LA’s role as an oncometabolite in hepatocellular carcinoma	[270]
Hepatocellular carcinoma	TCGA/ICGC multi-omics prognostic modeling	High LA metabolic activity (gene expression signature) correlated with reduced survival and more aggressive tumor phenotypes. LA-related metabolic pathways proposed as therapeutic targets	[271]
Gastric adenocarcinoma	EPIC-EURGAST (plasma phospholipids)	No significant association between plasma LA and gastric cancer risk. Very limited range of dietary intake in cohort; < 5% energy LA group not present	[272]
Cervical	Radiotherapy cohort (serum + fecal metabolomics)	Patients with low serum and fecal LA at baseline showed poorer nutritional status and worse treatment response. Unclear if LA was causally protective or a marker of overall intake	[273]

ER: Estrogen receptor; LA: Linoleic acid; CYP: Cytochrome P450; EPIC: European Prospective Investigation into Cancer and Nutrition; TCGA: The Cancer Genome Atlas; ICGC: International Cancer Genome Consortium; EURGAST: European Gastric Cancer Study; PPARα: Peroxisome proliferator-activated receptor-alpha.