Epidemiological studies report inconsistent findings regarding the association between dietary polyunsaturated fatty acid (PUFA) intake and cancer risk. Genetic variations—particularly single-nucleotide polymorphisms (SNPs) in the FADS1 and FADS2 genes—affect PUFA metabolism, linking circulating PUFA levels to the risk of several cancers, including breast, colorectal, prostate, and pancreatic cancers. This review aimed to investigate the relationship between FADS1 and FADS2 gene variants and dietary intake, supplementation, or intervention with omega-3 fatty acids, gamma-linolenic acid (GLA), or their combination in cancer patients. A secondary objective was to examine genetically determined fatty acid profiles—shaped by FADS1 and FADS2 polymorphisms—in cancer patients without intervention and their potential association with PUFA-related cancer risk. A systematic search of the Scopus, PubMed, and Web of Science databases (up to 2024) identified 11 eligible studies out of 298 initial records. Analysis of the available literature suggests that specific FADS genotypes influence long-chain PUFA (LC-PUFA) concentrations in blood and tissues and that altered LC-PUFA levels may contribute to cancer development. The most consistent association identified is between the rs174537 variant and altered PUFA metabolism in prostate and breast cancer. However, conclusive evidence is lacking on the impact of dietary patterns on FADS desaturase activity or expression. Only one study has examined omega-3 supplementation in relation to FADS gene variants in prostate cancer patients, while the effects of GLA supplementation remain unexplored. Given the relative novelty of this research area and the limited number of studies, future investigations should integrate dietary PUFA intake, genetic variation in PUFA-metabolizing enzymes, and potential gene–nutrient interactions involving FADS gene polymorphisms and PUFAs to clarify their role in cancer risk.