Credit:www.freepik.com

Cancer remains a significant global health challenge, and understanding the complex interactions between diet, metabolism, and immune responses is crucial for developing effective treatments. In a recent study published in Cell Metabolism, a team of researchers led by Dr. Qiang Zou from Shanghai Jiao Tong University investigated the impact of dietary fructose on antitumor immune responses using murine models and human clinical data. The study revealed a novel mechanism by which fructose, a common component of high-sugar diets, could enhance the function of CD8+ T cells, a key component of the immune system's antitumor response.

CD8+ T cells are specialized immune cells that recognize and destroy cancer cells. They play a crucial role in tumor control by directly killing cancer cells or activating other immune cells. However, CD8+ T cells often become exhausted in the tumor microenvironment, leading to immune escape and tumor progression. Strategies to reinvigorate exhausted CD8+ T cells have shown promise in cancer immunotherapy, but the underlying mechanisms and factors that influence CD8+ T cell function remain understudied.

Previous studies have suggested that high fructose consumption can promote tumor growth and metastasis in mice. However, the impact of fructose on antitumor immune responses is less clear. A recent study conducted by Zhang et al. aimed to explore whether dietary fructose could influence the function of CD8+ T cells and, consequently, antitumor immunity.

The researchers used murine models of melanoma, lung cancer, and colon cancer to investigate the effects of high-fructose diets on tumor growth and CD8+ T cell function. They found that high-fructose diets significantly suppressed tumor growth and delayed tumor progression in all three models. Single-cell RNA sequencing of tumor-infiltrating CD8+ T cells revealed that fructose consumption resulted in a shift towards a more active and less exhausted CD8+ T cell population, characterized by a higher proportion of proliferating and effector cells and a lower proportion of exhausted cells.

To further investigate the mechanism underlying these effects, the researchers explored the role of leptin, a hormone produced by adipocytes (fat cells). They found that high-fructose diets induced the production of leptin in adipocytes, which was crucial for the enhanced CD8+ T cell function observed. Leptin signaling pathways were found to be activated in the tumor microenvironment of mice fed a high-fructose diet, and blocking leptin signaling reversed the antitumor effects of fructose.

The researchers then investigated how fructose metabolism regulated leptin expression in adipocytes. They found that fructose activated the mTORC1 signaling pathway, a key regulator of cellular metabolism and growth. mTORC1 activation promoted the expression of genes involved in lipid metabolism, including leptin. Knockout studies in adipocytes confirmed that mTORC1 was essential for fructose-induced leptin production.

The researchers also explored the clinical relevance of the fructose-leptin axis in cancer patients. They found that higher plasma leptin levels were associated with improved antitumor T cell responses in patients with lung cancer, but not in patients with colorectal cancer. This suggested that the fructose-leptin axis might play a more significant role in lung cancer immunity.

The study revealed a previously unrecognized role for dietary fructose in shaping adipocyte metabolism to enhance CD8+ T cell function and control tumor growth. The fructose-leptin axis represents a potential target for enhancing antitumor immunity, particularly in lung cancer. Further research is needed to explore the clinical applications of this discovery and to determine the impact of fructose on other aspects of cancer immunity and metabolism.

On the contrary, another study conducted by Zhou et al. investigated the role of dietary fructose in promoting the progression of hepatocellular carcinoma (HCC), a common and aggressive liver cancer. The authors employed a comprehensive approach, combining metabolomics, stable isotope tracing, and targeted proteomics, to uncover a novel mechanism through which fructose enhanced O-GlcNAcylation, a post-translational modification that modulated protein function and contributed to cancer progression.

The research began by demonstrating that supplementing the diet of mice with high fructose accelerated the development and severity of HCC, even when the mice were fed a standard diet without excess calories or fat. This suggested that fructose itself, rather than its associated metabolic disturbances, played a direct role in promoting HCC.

The authors then focued on O-GlcNAcylation, a modification that could increase the stability and activity of proteins in response to nutrient availability. They found that fructose supplementation led to increased levels of UDP-GlcNAc, the substrate for O-GlcNAcylation, and enhanced O-GlcNAcylation in HCC cells. Furthermore, they demonstrated that targeting O-GlcNAcylation through the depletion of OGT, the enzyme responsible for adding the O-GlcNAc group, significantly impaired HCC progression.

To understand the mechanism by which fructose promoted O-GlcNAcylation, the researchers investigated the role of acetate, a product of fructose metabolism by the gut microbiota. They found that fructose intake increased acetate levels in the portal vein, and that acetate enhanced O-GlcNAcylation and promotes HCC growth. This suggested that acetate played a critical role in mediating the effects of fructose on HCC.

The study further identified the enzyme glutamine synthetase (GLUL) as a key player in acetate-mediated O-GlcNAcylation. GLUL converted acetate into glutamate, which was then used to produce UDP-GlcNAc. Knocking down GLUL in HCC cells reduced UDP-GlcNAc levels and impaired HCC progression, further highlighting its importance in this process.

To gain a broader understanding of the impact of fructose on O-GlcNAcylation, the researchers performed a global O-GlcNAcylation profiling analysis. They identified several proteins that underwent increased O-GlcNAcylation in response to fructose, including the translation elongation factor eEF1A1 and the cysteine protease CAPNS1. These proteins were associated with cell proliferation and tumor growth, suggesting that their O-GlcNAcylation contributed to the effects of fructose on HCC.

Overall, this study provided compelling evidence that dietary fructose promoted HCC progression by enhancing O-GlcNAcylation via microbiota-derived acetate. The research highlighted the importance of GLUL in this process and suggested that targeting OGT or GLUL might represent a promising therapeutic strategy for HCC. The findings also shed light on the complex interplay between dietary fructose, gut microbiota, and cancer metabolism, offering valuable insights for the development of new approaches to prevent and treat HCC.

Reference:

1. Zhang Y, Yu X, Bao R, Huang H, Gu C, Lv Q, Han Q, Du X, Zhao XY, Ye Y, Zhao R, Sun J, Zou Q. Dietary fructose-mediated adipocyte metabolism drives antitumor CD8+ T cell responses. Cell Metab. 2023 Dec 5;35(12):2107-2118.e6.

2. Zhou P, Chang WY, Gong DA, Xia J, Chen W, Huang LY, Liu R, Liu Y, Chen C, Wang K, Tang N, Huang AL. High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-GlcNAcylation via microbiota-derived acetate. Cell Metab. 2023 Nov 7;35(11):1961-1975.e6.