# Lipid Metabolism Reprogramming in Diffuse Large B-Cell Lymphoma (DLBCL): Mechanisms and Treatment Strategies

## TL;DR

This review explores how changes in lipid metabolism drive DLBCL progression and resistance to treatment, offering new strategies for targeting these processes to improve patient outcomes.

## Contribution

The paper provides a comprehensive overview of lipid metabolism reprogramming and its interplay with ferroptosis and the tumor immune microenvironment in DLBCL.

## Key findings

- Aberrant lipid metabolism promotes tumor growth and suppresses ferroptosis in DLBCL.
- Metabolic crosstalk between lymphoma cells and immune cells contributes to immunosuppression and treatment resistance.
- Targeting lipid metabolism and the tumor immune microenvironment offers potential for new therapeutic strategies.

## Abstract

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous and aggressive malignancy, in which relapse and therapeutic resistance remain major clinical challenges. Growing evidence indicates that lipid metabolism reprogramming serves as a central driver of DLBCL progression, treatment resistance, and immune evasion. Aberrant fatty acid, cholesterol, and phospholipid metabolism promotes tumor growth, suppresses ferroptosis, and remodels the tumor immune microenvironment (TIME). Key metabolic enzymes and pathways, including FASN, FAO-related enzymes, the PI3K–AKT–mTOR signaling axis, and ceramide metabolism, are closely associated with ferroptosis susceptibility and immune cell function. Furthermore, metabolic crosstalk between lymphoma cells and immune components, such as macrophages and T cells, contributes to immunosuppression and resistance to immunotherapy. This review summarizes recent advances in lipid metabolism reprogramming, ferroptosis regulation, and TIME remodeling in DLBCL, and outlines prognostic biomarkers and therapeutic strategies targeting lipid metabolism, ferroptosis, and the tumor immune microenvironment, thereby providing new insights for improving treatment outcomes.

Diffuse large B-cell lymphoma (DLBCL) is a common, aggressive non-Hodgkin lymphoma with significant molecular heterogeneity. This variability arises in part from its distinct molecular subtypes, including germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL), which differ markedly in their genetic profiles, signaling pathway activities, and clinical outcomes. Although rituximab-based R-CHOP regimens have significantly improved patient outcomes, around 40% of patients still experience relapsed or refractory disease. DLBCL cells sustain their rapid proliferation through the establishment of an intricate lipid metabolism regulatory network. The interplay between this network, cell death mechanisms (e.g., ferroptosis), and the tumor immune microenvironment (TIME) significantly impacts the malignant progression of the disease and its resistance to treatment. This review summarizes recent advances in understanding the molecular mechanisms and interplay among these processes in DLBCL and discusses the clinical relevance of associated prognostic biomarkers, thus providing new insights into the development of precision therapies.