ArticleCancer research2022
Ketogenesis Attenuates KLF5-Dependent Production of CXCL12 to Overcome the Immunosuppressive Tumor Microenvironment in Colorectal Cancer.
Article in Cancer research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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57 citing papers in PubMed, 103 citations in OpenAlex.
- Ketogenic Diet: A Metabolic Key to Overcoming Cancer Therapy Resistance.Molecular nutrition & food research · 2026Review
- Reverse cardio-oncology: neuroendocrine axis activation and cardiovascular-disease-derived factors synergistically remodel the tumor microenvironment.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Cancer-associated fibroblasts and tertiary lymphoid structure orchestrate the spatial architecture of tumor immunity.Journal of hematology & oncology · 2026Review
- PRKN mediates the ubiquitination of SCAF8 to reduce the mRNA stability of KLF5 and its transcriptional activation of EFNA3 in colorectal cancer.Cellular & molecular biology letters · 2026Article
- β-hydroxybutyrate potentiates anti-tumor immunity by modulating cytotoxic CD8Cancer immunology, immunotherapy : CII · 2026Article
- ETV4 Promotes Colorectal Cancer Progression by Reprogramming Asparagine Metabolism to Remodel the Stromal Microenvironment.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Radiation-activated astrocytes promote tumor progression through CXCL12 secretion and induce resistance to anti-PD-1 immunotherapy.Translational cancer research · 2026Article
- CXCL12-mediated T cell infiltration drives breast cancer metastasis.Clinical and experimental medicine · 2026Article
- Nutritional modulation of metabolic signaling within the tumor microenvironment for cancer therapy.Molecular and cellular biochemistry · 2026Review
- The research advances of crosstalk between cancer-associated fibroblasts and tumor cells using co-culture organoids.Cell death & disease · 2026Review
- Specific depletion of TIGITJournal for immunotherapy of cancer · 2026Article
- Cancer cachexia: molecular basis and therapeutic advances.Signal transduction and targeted therapy · 2026Review
- SIRT3 Regulates HMGCS2 Deacetylation and Influences Cholangiocarcinoma Progression via the Metabolism of Ketone Bodies.Human mutation · 2026Article
- Impact of PFAS exposure on lipid metabolic pathways: mechanisms and implicatins in carcinogenesis.Frontiers in toxicology · 2026Review
- Targeting immunometabolism in cancer through pharmacological and lifestyle interventions.PLoS biology · 2026Review
- CAFs mediate carboplatin resistance in LUAD via CXCL12 secretion regulated by NF-κB activation.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Cancer-associated fibroblast secreted DKK1 promotes the immunosuppressive tumor microenvironment and colorectal cancer resistance to chemotherapy.Cancer letters · 2025Article
- Gut microbiota in hepatocellular carcinoma immunotherapy: immune microenvironment remodeling and gut microbiota modification.Gut microbes · 2025Review
- Characterization of cis-regulatory elements and functional variants in colorectal cancer using epigenomics and CRISPRi screenings.Nature cancer · 2025Article
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13 authors at 2 institutions in 2 countries.
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Abstract
The dynamic composition of the tumor microenvironment (TME) can markedly alter the response to targeted therapies for colorectal cancer. Cancer-associated fibroblasts (CAF) are major components of TMEs that can direct and induce infiltration of immunosuppressive cells through secreted cytokines such as CXCL12. Ketogenic diets (KD) can inhibit tumor growth and enhance the anticancer effects of immune checkpoint blockade. However, the role of ketogenesis on the immunosuppressive TME is not known. Here, we show that decreased ketogenesis is a signature of colorectal cancer and that an increase in ketogenesis using a KD decreases CXCL12 production in tumors, serum, liver, and lungs. Moreover, increasing ketogenesis by overexpression of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) or treatment with the ketone body β-hydroxybutyrate markedly decreased expression of KLF5, which binds the CXCL12 promoter and induces CXCL12 expression in CAFs. KD decreased intratumoral accumulation of immunosuppressive cells, increased infiltration of natural killer and cytotoxic T cells, and enhanced the anticancer effects of PD-1 blockade in murine-derived colorectal cancer. Furthermore, increasing ketogenesis inhibited colorectal cancer migration, invasion, and metastasis in vitro and in vivo. Overall, ketogenesis is downregulated in the colorectal cancer TME, and increased ketogenesis represses KLF5-dependent CXCL12 expression to improve the immunosuppressive TME, which leads to the enhanced efficacy of immunotherapy and reduced metastasis. Importantly, this work demonstrates that downregulation of de novo ketogenesis in the TME is a critical step in colorectal cancer progression. SIGNIFICANCE: This study identifies ketogenesis as a critical regulator of the tumor microenvironment in colorectal cancer and suggests the potential for ketogenic diets as a metabolic strategy to overcome immunosuppression and prolong survival. See related commentary by Montrose and Galluzzi, p. 1464.
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