Omega-3 Polyunsaturated Fatty Acids in Cancer Cachexia and Inflammation: Mechanisms and Delivery Innovations

Cancer-associated cachexia and chronic systemic inflammation remain among the most challenging complications in oncology, impairing prognosis, treatment tolerability, and survival. This narrative review examines the mechanistic rationale and clinical evidence for omega-3 polyunsaturated fatty acids (PUFAs), principally eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as adjunctive nutritional and metabolic support agents in this setting, drawing on randomized controlled trials, systematic reviews, meta-analyses, and mechanistic studies, alongside the oral, enteral, parenteral, and nanotechnology-based platforms used to deliver these fatty acids. In experimental models, predominantly cancer cell lines and tumor-bearing rodents, EPA and DHA act on multiple oncological processes, including suppression of pro-inflammatory cytokine synthesis, remodeling of the tumor microenvironment, inhibition of tumor cell proliferation, induction of apoptosis, and attenuation of skeletal muscle catabolism via the ubiquitin-proteasome system and the IGF-1/PI3K/Akt/mTOR axis; in patients, the most consistent mechanistic correlate is a reduction in circulating inflammatory biomarkers. Bioavailability varies substantially by molecular form, with re-esterified triglycerides outperforming ethyl esters and emerging micellar and phospholipid nanoformulations achieving markedly higher absorption in pharmacokinetic and preclinical studies. In advanced non-small cell lung cancer with established cachexia, a meta-analysis of small randomized trials suggests that at least 2 g EPA+DHA per day for six weeks or more may yield modest gains in body weight and quality-of-life scores; this signal, however, derives mainly from pooled analyses and has not been consistently reproduced in individual trials, including large negative trials in mixed cancer populations. Across broader oncological populations, reduction in inflammatory biomarkers is the most consistent finding, effects on chemotherapy tolerability are suggestive but of low certainty, and effects on lean mass and overall survival remain inconclusive. Consistent with ESPEN and ESMO guidance, omega-3 PUFAs should be regarded as metabolic and nutritional support within multimodal cachexia care, not as an anticancer treatment. Omega-3 PUFAs are a biologically grounded and potentially useful, but not yet clinically established, intervention in oncological nutrition, but adequately powered trials with harmonized endpoints, standardized formulations, and stratification by cancer type and cachexia stage are still needed to translate this mechanistic signal into definitive therapeutic protocols.