Integrated fatty acid profiling unveils a linkage between BMI and efficacy of anti-tumor immunotherapy

/ABSTRACT Immunotherapy has proven effective against cancer, but it encounters challenges in overcoming resistance and maximizing efficacy. Identifying substances to enhance immunotherapies is crucial. Paradoxically, emerging evidence suggests a link between mild obesity and improved outcomes in cancer patients treated with immune checkpoint inhibitors (ICIs). Considering that circulating free fatty acids (FFAs) can impact various immune cells and serum FFA levels are elevated in obesity, we hypothesize that certain circulating FFAs may serve as immunomodulators, enhancing anti-tumor immunity for improved cancer treatment. We systematically compare the levels of FFAs in the serum of 43 melanoma patients who responded or did not respond to ICI therapy. Additionally, we curated a library of 62 commercially available FFAs present in the human body to identify those enhancing immune cell functions. Applying these approaches, we revealed the crucial role of essential fatty acids (EFAs) in regulating CD8+ T cells, thereby boosting anti-tumor immunity. We discovered that six FFAs within the EFA pathway significantly influenced CD8+ T cells. Arachidonic acid (AA), Eicosapentaenoic acid (EPA), and Docosahexaenoic acid (DHA) enhanced immune responses, while Linoleic acid (LA), γ-Linolenic acid (GLA), and α-Linolenic acid (ALA) had inhibitory effects. Notably, the EFAs promoting immunity are positioned downstream in the EFA pathway (DEFA), while those inhibiting immunity are situated upstream in the EFA pathway (UEFA). We observed that the oral administration of DEFAs enhances anti-tumor immunity, whereas UEFAs promote tumor growth in vivo. Our mechanistic studies reveal that the EFAs effects on CD8+ T cells are through GPCR. DEFAs have a different interaction pattern with GPR120 compared to UEFAs. I thus hypothesize that the differential structural interactions of DEFAs and UEFAs with GPR120 contribute to reprogramming CD8+ T cells and anti-tumor immunity. Three specific aims are: (1) To investigate whether DEFAs and UEFAs distinctly modulate CD8+ T cell function and impact anti-tumor immunity in vivo, both individually and in combination with ICI. Additionally, we aim to measure serum EFA levels in lymphoma patients treated with CAR T-cell therapy. (2) To validate whether GPR120 is the target of EFAs in CD8+ T cell regulation, and to delve into the structural-based mechanisms underlying the distinct regulatory effects of DEFAs and UEFAs on CD8+ T cells through GPR120. Moreover, we will perform structure-activity research (SAR) studies and design new derivatives of DEFAs with improved potency and efficacy to enhance CD8+ T cell function and anti-tumor immunity. (3) To investigate the impact of FFAs on diverse immune cells, encompassing CD4+ T cells, dendritic cells (DCs), natural killer (NK) cells, and innate lymphoid (ILC) cells, as well as their implications for anti-tumor immunity. Project Number: 1K99CA297133-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Hao Fan | Institution: UNIVERSITY OF CHICAGO, CHICAGO, IL | Award Amount: $129,285 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 CDPT-N (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11281670