Lipid metabolic reprogramming and the tumor immune microenvironment

Introduction

Abnormal lipid metabolism has emerged as a fundamental feature in cancer biology. Tumor cells exploit lipid metabolic pathways to support rapid proliferation, evade immune surveillance, and manipulate the TIME. The acidic and hypoxic environment of tumors exacerbates immune dysfunction, enabling immune evasion. Thus, understanding lipid metabolism in tumors is essential for developing new strategies for early screening and immunotherapy.

 

Lipid Metabolism in Tumor Cells

Lipids are central to cell membrane composition, signal transduction, and energy storage. Tumor cells reprogram lipid pathways to meet elevated metabolic demands. Major lipid classes such as fatty acids, cholesterol, and lipid droplets are involved in this process.

Fatty Acids

Tumors often rely on de novo fatty acid synthesis and upregulate enzymes like ATP citrate lyase and acyl-CoA synthetase. Fatty acid oxidation (FAO) promotes invasion and metastasis, while the saturation state of fatty acids influences membrane dynamics and cell signaling. These metabolic adaptations enhance tumor growth and therapy resistance.

Cholesterol

Cholesterol supports membrane integrity and signaling. Tumors often overexpress enzymes involved in cholesterol esterification, such as ACAT, leading to lipid droplet accumulation. This process supports tumor progression and is regulated by pathways like SREBP2, Hedgehog, and Notch.

Lipid Droplets

Lipid droplets store excess fatty acids and cholesterol. Dysregulation of lipid droplet metabolism, through proteins like PLIN2 and transcription factors such as FOXO3, influences tumor growth, oxidative stress, and cell survival. Lipophagy and lipolysis contribute to ROS production, which can be exploited by tumor cells.

 

Lipids and the Tumor Immune Microenvironment

Lipid metabolism shapes the function and fate of immune cells in the TIME. Metabolic competition and suppression by tumor cells hinder effective immune responses.

T Cells

CD4+ and CD8+ T cells adapt metabolically to the tumor environment. Regulatory T cells (Tregs) rely on FAO and oxidative phosphorylation (OXPHOS) for survival, contributing to immunosuppression. Effector T cells are more dependent on glycolysis and can be impaired by nutrient depletion and ROS.

Dendritic Cells (DCs)

DC function is inhibited by lipid overload in the TIME. High lipid content impairs antigen presentation, while FAO inhibition can restore DC activity. Targeting cholesterol metabolism may reverse DC tolerance and enhance immunotherapy.

Myeloid-Derived Suppressor Cells (MDSCs)

MDSCs utilize FAO and arachidonic acid metabolism (via FATP-2) to suppress T cells. Inhibiting these pathways reactivates immune responses and delays tumor growth.

NK Cells and Macrophages

NK cells depend on lipid metabolism for cytotoxicity. The mTOR pathway regulates their antitumor activity. Macrophages exhibit dual roles: M1 macrophages are pro-inflammatory, while M2 macrophages (TAMs) promote tumor growth via FAO and cytokine secretion (e.g., IL-10, TGF-β).

 

Lipid Metabolism Markers in Cancer

Lipid metabolism-related molecules serve as potential biomarkers for early cancer detection. Markers such as FASN, FATP, ceramides, oxysterols, and LPC correlate with tumor development and immune modulation. These markers guide diagnosis, prognosis, and treatment decisions.

 

Lipid Metabolism in Cancer Screening and Prevention

Metabolites like fatty acids and cholesterol reflect early tumorigenic changes. Their measurement in blood or tissue can support early screening. Modifying lipid metabolism—e.g., inhibiting FA synthesis or enhancing FAO—may prevent tumor initiation.

 

Lipid Metabolism and Immunotherapy

Combining lipid-targeting therapies with immune checkpoint inhibitors enhances antitumor efficacy. CD36 inhibitors, for instance, reduce lipid uptake and alleviate immunosuppression. Lipid-based drug delivery systems (e.g., liposomes) improve therapeutic targeting. The review also highlights ferroptosis, an iron-dependent cell death pathway driven by lipid peroxidation, as a novel target in cancer therapy.

 

Future Perspectives

Future research should focus on:

1. Developing clinically applicable lipid metabolism markers.
2. Optimizing lipid-based drug delivery systems.
3. Integrating immunometabolism into precision oncology.
   Combining lipid metabolism modulation with immunotherapies promises improved outcomes and more personalized cancer prevention strategies.

 

Conclusion

Lipid metabolism plays a crucial role in tumorigenesis and immune regulation. Its reprogramming not only supports cancer cell survival but also impairs antitumor immunity. Targeting lipid metabolic pathways offers innovative strategies for early diagnosis, prevention, and immunotherapy of cancer. Continued exploration of these mechanisms will be vital for next-generation cancer interventions.

 

Full text

https://www.xiahepublishing.com/2835-3315/CSP-2025-00002

 

The study was recently published in the Cancer Screening and Prevention.

Cancer Screening and Prevention (CSP) publishes high-quality research and review articles related to cancer screening and prevention. It aims to provide a platform for studies that develop innovative and creative strategies and precise models for screening, early detection, and prevention of various cancers. Studies on the integration of precision cancer prevention multiomics where cancer screening, early detection and prevention regimens can precisely reflect the risk of cancer from dissected genomic and environmental parameters are particularly welcome.

 

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