Fatty Acid Heterogeneity in Colorectal Cancer: From Food Matrices to Targeted Interventions

Fatty acids are dietary exposures, membrane components, signaling precursors, and products of endogenous metabolism. Their relationship with colorectal cancer (CRC) is therefore difficult to interpret because dietary intake, circulating and erythrocyte biomarkers, tumor tissue, genetically predicted levels, and interventions represent different biological phenomena. This structured narrative review integrates these domains to explain heterogeneous associations with CRC risk, precursor lesions, progression, and clinical outcomes. Human evidence does not support a simple classification in which saturated fatty acids (SFAs) and n-6 polyunsaturated fatty acids (n-6 PUFAs) are uniformly harmful, monounsaturated fatty acids (MUFAs) are neutral, and n-3 polyunsaturated fatty acids (n-3 PUFAs) universally protective. Associations vary by individual fatty acid, food source, biological matrix, endogenous desaturation and elongation, tumor site, sex, stage, and study design. Circulating n-3 PUFA biomarkers show several inverse associations, including prospective UK Biobank evidence, but relationships may be nonlinear and site- and sex-specific. Tumor lipid profiles demonstrate metabolic remodeling but cannot establish causal exposure. Mendelian randomization provides complementary evidence but is sensitive to pleiotropy and metabolic correlation. Intervention studies suggest benefits for selected perioperative, inflammatory, immune, or nutritional outcomes, whereas evidence for adenoma prevention, CRC recurrence, or survival remains limited. Interpretation should therefore consider the distinct evidence domains rather than total fat classes or the n-6/n-3 PUFA ratio alone.