Cancer Cells Evade Immune Cell-Induced Ferroptosis via Fatty Acid Binding Protein 7

Background Introduction

Cancer creates an immunosuppressive environment that hinders immune responses, allowing tumors to grow and resist treatment. The immune system combats this by inducing ferroptosis in tumor cells through CD8+ T cells. Ferroptosis is a type of cell death characterized by iron-dependent lipid peroxidation and reactive oxygen species (ROS) accumulation. However, the mechanisms by which cancer cells evade ferroptosis induced by immunotherapy remain unclear. This study uncovers how cancer cells escape ferroptosis and anti-tumor immunity by upregulating fatty acid binding protein 7 (FABP7).

FABP7 is a protein primarily expressed in the brain, involved in fatty acid metabolism and transport, especially in neural stem cells and neurogenesis. Previous studies have shown that FABP7 is highly expressed in various cancers and correlates with poor prognosis. However, its specific role in regulating ferroptosis and its impact on immunotherapy has not been fully explored. This study aims to elucidate the precise mechanism by which FABP7 enables tumor cells to evade immune-mediated ferroptosis and identify new therapeutic targets to enhance immunotherapy efficacy.

Paper Source

This study was conducted by Maria Angelica Freitas-Cortez and over twenty co-authors from institutions such as UT Southwestern Medical Center and MD Anderson Cancer Center. The findings were published in Molecular Cancer in 2025 under the title “Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins.”

Research Process and Experimental Design

Overview of Research Process

The study employed multiple steps, combining in vitro cell experiments and in vivo mouse models with high-throughput sequencing, lipidomics analysis, and immunohistochemistry to systematically explore the role of FABP7 in tumor cells evading ferroptosis. Below is the detailed process:

1. Cell Line and Mouse Model Establishment

   • The study used PD1-sensitive (PD1-sensitive, Sen) and PD1-resistant (PD1-resistant, Res) tumor cell lines, along with B16F10 melanoma cells and QPP7 glioblastoma cells. Mouse models included 129 Sv/Ev and C57BL/6 strains, and genetically edited mice with CD8+ T cell-specific Rora knockout were also created.

2. Lipidomics Analysis

   • Mass spectrometry was used to comprehensively analyze lipid metabolism in Sen and Res tumors treated with PD1 inhibitors. Oil Red O staining confirmed increased lipid accumulation in Res tumors.

3. Targeted Lipidomics and Fatty Acid Oxidation Analysis

   • Liquid chromatography-mass spectrometry (LC-MS) quantified eicosanoids and fatty acid metabolites in tumors. Seahorse analysis assessed mitochondrial fatty acid oxidation (FAO) function.

4. Omics Analysis and Epigenetic Studies

   • RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyzed gene expression and epigenetic modifications in Res and Sen tumors, revealing FABP7’s regulation of ferroptosis-related genes like Lpcat3 and Bmal1.

5. Immune Cell and Tumor Cell Co-culture Experiments

   • In vitro co-culture experiments examined FABP7’s effects on CD8+ T cell apoptosis and circadian clock gene expression, using ATAC-seq and RNA-seq to analyze FABP7’s transcriptional regulation in T cells.

6. Flow Cytometry and Immunohistochemistry Analysis

   • Flow cytometry measured CD8+ T cell apoptosis rates, while immunohistochemistry validated FABP7’s impact on lipid peroxidation and immune cell infiltration in the tumor microenvironment.

7. In Vivo Experiment Verification

   • In 129 Sv/Ev and C57BL/6 mouse models, injecting Res and Res-shFABP7 cells evaluated the effect of FABP7 knockdown on tumor growth and sensitivity to immunotherapy.

Key Results and Logical Relationships

1. Lipid Metabolic Reprogramming in PD1-Resistant Tumors

   • Lipidomics analysis showed that Res tumors treated with PD1 inhibitors had significantly elevated levels of triglycerides (TGs) and monounsaturated fatty acids (MUFAs), while polyunsaturated fatty acids (PUFAs) decreased. This metabolic shift made tumor cells more resistant to ferroptosis. Seahorse analysis further indicated enhanced mitochondrial FAO capacity and ATP production in Res cells.

2. Upregulation of FABP7 and Epigenetic Regulation

   • RNA-seq and ChIP-seq analyses revealed significant upregulation of FABP7 in Res tumors, which regulated ferroptosis-related gene expression through epigenetic modifications. Specifically, FABP7 reduced Lpcat3 transcription and increased Bmal1 expression, thereby inhibiting ferroptosis.

3. Impact of FABP7 on Immune Cells

   • Co-culture experiments found that FABP7 in Res tumors upregulated FABP7 expression in CD8+ T cells, disrupting circadian clock gene expression and promoting T cell apoptosis. ATAC-seq and RNA-seq analyses further elucidated FABP7’s induction of T cell apoptosis via the Rora and p53 pathways.

4. Enhanced Sensitivity to Immunotherapy Following FABP7 Knockdown

   • In 129 Sv/Ev and C57BL/6 mouse models, FABP7 knockdown significantly increased tumor sensitivity to PD1 inhibitors, boosting CD8+ T cell infiltration into the tumor microenvironment and reducing T cell apoptosis.

Conclusion and Significance

This study reveals the critical role of FABP7 in enabling tumor cells to evade immune-mediated ferroptosis. By reprogramming lipid metabolism, modulating epigenetics, and reshaping the immune microenvironment, FABP7 promotes tumor cell survival and resistance to immunotherapy. The findings provide a theoretical basis for developing targeted therapies against FABP7, potentially enhancing immunotherapy efficacy, particularly in PD1-resistant tumors.

Research Highlights

1. Novel Insights into Multiple Roles of FABP7 in Tumor Immune Evasion

   • For the first time, this study systematically elucidates how FABP7 facilitates tumor cell evasion of immune-induced ferroptosis through lipid metabolism, epigenetic, and immune regulation mechanisms.

2. High-Throughput Multi-Omics Analysis

   • Utilizing RNA-seq, ChIP-seq, ATAC-seq, and lipidomics, the study provides a comprehensive molecular mechanism analysis of FABP7.

3. Discovery of a Novel Therapeutic Target

   • The study proposes FABP7 as a potential therapeutic target, offering a new direction to overcome resistance to cancer immunotherapy.

Additional Valuable Information

The study also uncovered the mechanism by which FABP7 regulates circadian clock genes to influence CD8+ T cell function, providing new insights into the biology of immune cells in the tumor microenvironment. This discovery may inspire cancer immunotherapy strategies based on circadian rhythm modulation.