Abstract Diet is a key factor that shapes the gut microbiome, systemic metabolism and immune function. However, how specific macronutrients alter host physiology and tumor-immune interactions relevant to tumor progression and response to immune checkpoint inhibitor (ICI) immunotherapy remains unclear. We therefore sought to investigate how high fat diets (HFDs) varying in macronutrient source and composition influence metabolism, the gut microbiome and anti-tumor immunity. C57BL/6 mice were fed either a standard chow (CD), high fat (HF)/high sugar (HS)-Copha or HF-Lard diet for 2 or 7 weeks prior to inoculation with a syngeneic cancer cell line. These diets notably have differing fatty acid compositions; the copha-based (plant) HFD has more MCFAs compared to the lard-based (animal) HFD that is dominated by LCFAs. Mice on HF-Lard exhibited impaired glucose tolerance and reduced insulin sensitivity compared to CD and HF/HS-Copha after 2 and 7 weeks on diets. However, only mice on HF-Lard longer term had both elevated fasting glucose and insulin. Profiling the gut microbiomes of mice revealed both HFDs rapidly induced gut dysbiosis characterized by reduced diversity, although HF/HS-Copha compared to HF-Lard were enriched with metabolically beneficial species Blautia coccoides, Parabacteroides merdae and Bacteroides acidifaciens. Notably, HF-Lard accelerated the growth of B16-F10 and YUMM3.3-UVR melanomas while both HFDs accelerated the growth of MC38 colorectal adenocarcinomas. Similar results were observed in the short-term study except for B16-F10 where no differences between diets were observed. This suggests the acceleration is independent of obesity though may be influenced by the immunogenicity or intrinsic insulin sensitivity of the tumor. Spectral flow analysis of immune cells across the mesenteric lymph nodes (MLN), spleen, tumor draining LN (tdLN) and tumor revealed divergent immune profiles across diets. Both HFDs had lower plasma cells, cDC1s and CD8 T cells in the tdLN compared to CD. However, HF-Lard mice had higher frequencies of monocytes, and both Th17 cells and RORgt+ Tregs, indicating polarization towards suppressive phenotypes in addition to impaired anti-tumor priming. This was accompanied by enhanced exhaustion across CD8 T cells in the tumors of HF-Lard mice.Together this suggests that HFDs dominated by LCFAs are associated with metabolic dysfunction, and altered microbiome and immune phenotypes, which could contribute to accelerated tumor growth for melanoma. It also highlights that tumor type/genetics are important factors in how the diet-gut axis influences tumor growth. Ongoing work will focus on understanding how specific fat sources and diet durations impact ICI treatment and ultimately inform the design of more specific dietary interventions to enhance the efficacy of treatment. Citation Format: Rebecca C. Simpson, Freya E. Edge, Jordan W. Conway, Hsin-Yi Tseng, Mirei Okada, Inah Camaya, Laura Smith, Akshaya Ramanathan, Oliver K. Fuller, Stewart W. Masson, Jessamy Tiffen, Georgina V. Long, Erin R. Shanahan. The impact of high fat diet on tumor growth is dependent on fatty acid composition and tumor type abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2882.
Simpson et al. (Fri,) studied this question.