Lipid accumulation in macrophages confers protumorigenic polarization and immunity in gastric cancer
Open accessAbstract
Heterotypic interactions between tumor cells and macrophages can enable tumor progression and hold potential for the development of therapeutic interventions. However, the communication between tumors and macrophages and its mechanism are poorly understood. Here, we find that tumor‐associated macrophages (TAM) from tumor‐bearing mice have high amounts of lipid as compared to macrophages from tumor‐free mice. TAM also present high lipid content in clinical human gastric cancer patients. Functionally, TAM with high lipid levels are characterized by polarized M2‐like profiling, and exhibit decreased phagocytic potency and upregulated programmed death ligand 1 (PD‐L1) expression, blocking anti–tumor T cell responses to support their immunosuppressive function. Mechanistically, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identifies the specific PI3K pathway enriched within lipid‐laid TAM. Lipid accumulation in TAM is mainly caused by increased uptake of extracellular lipids from tumor cells, which leads to the upregulated expression of gamma isoform of phosphoinositide 3‐kinase (PI3K‐γ) polarizing TAM to M2‐like profiling. Correspondingly, a preclinical gastric cancer model is used to show pharmacological targeting of PI3K‐γ in high‐lipid TAM with a selective inhibitor, IPI549. IPI549 restores the functional activity of macrophages and substantially enhances the phagocytosis activity and promotes cytotoxic‐T‐cell‐mediated tumor regression. Collectively, this symbiotic tumor‐macrophage interplay provides a potential therapeutic target for gastric cancer patients through targeting PI3K‐γ in lipid‐laden TAM.
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Reversing the lipid-laden phenotype of tumoral macrophages suppresses gastric cancer development.
“In line with this proposed strategy, reversing the lipid-laden phenotype of tumoral macrophages has already been successfully used to suppress the development of gastric cancer (62).”
From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [62]
The Results section reports that PI3K-γ inhibition reduced lipid accumulation in tumor-associated macrophages and significantly delayed tumor growth in an MFC gastric cancer mouse model. This supports a preclinical effect, but the citing sentence's suggestion that the strategy has already been successfully used to suppress gastric cancer development is broader than the demonstrated mouse-model result; the Discussion describes clinical use as a future prospect. (LLM, conf=0.86)
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- Authors
- Luo, Q., Zheng, N., Jiang, L., Wang, T., Zhang, P., Liu, Y., Zheng, P., Wang, W., Xie, G., Chen, L., Li, D., Dong, P., Yuan, X., & Shen, L.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Yuan, Xiangliang
- Shen, Lisong
- ORCID
- Venue
- Cancer Science
- Publisher
- Wiley
- Published
- 2020-09-18
- Volume
- 111
- Issue
- 11
- Pages
- 4000-4011
- ISSN
- 1347-9032 (ISSN-L)
- 1349-7006
- PMC
- PMC7648032
- OpenAlex
- W3049344485
- Cited by
- 126
- References
- 37
- Citations by year
- 2026: 21 · 2025: 26 · 2024: 32 · 2023: 21 · 2022: 21 · 2021: 4 · 2013: 1
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancer Science (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81372641, 81402148, 81472244, 81672363, 81772525)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- tumor-associated macrophages, gastric cancer, lipid accumulation, macrophage polarization, M2 macrophages, PI3Kγ, PD-L1, tumor immunosuppression, phagocytosis, tumor-macrophage interaction, cytotoxic T lymphocytes
- MeSH terms
- Lipidomics, Tumor-Associated Macrophages, Animals, Cell Transformation, Neoplastic, Disease Models, Animal, Disease Susceptibility, Female, Fluorescent Antibody Technique, Humans, Macrophage Activation, Macrophages, Models, Biological, Phagocytosis, Stomach Neoplasms, Immunophenotyping, T-Lymphocyte Subsets, Phosphatidylinositol 3-Kinases, Cell Line, Tumor, Lipid Metabolism, Mice, Tumor Microenvironment
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