# PLA2G16‐Mediated Tetracosatetraenoic Acid Rewires Fatty Acid Oxidation to Impair CD8+ T Cell Immune Function in Promoting Breast Cancer Lung Metastasis

## TL;DR

A tumor enzyme called PLA2G16 produces a fatty acid that weakens immune cells, helping breast cancer spread to the lungs.

## Contribution

Identifies a novel metabolic pathway involving PLA2G16 and C24:4 (n-6) that impairs CD8+ T cell function in breast cancer metastasis.

## Key findings

- PLA2G16 increases tetracosatetraenoic acid (C24:4 (n-6)) in the lung metastatic niche.
- C24:4 (n-6) activates PPARα in CD8+ T cells, promoting fatty acid oxidation and immune suppression.
- Blocking PLA2G16 or PPARα restores CD8+ T cell function and anti-tumor immunity.

## Abstract

Tumor‐related metabolites in the tumor microenvironment may induce immune dysfunction, leading to malignant progression and metastasis of tumors. Here, it is demonstrated that tumoral PLA2G16, a phospholipase catalyzes phospholipids to generate free fatty acid (FFA) or lysophosphatidic acid (LPA), is an important contributor to triple‐negative breast cancer (TNBC) lung metastasis in an immune‐dependent pattern by improving tetracosatetraenoic acid (C24:4 (n‐6)) accumulation in the early metastatic niche of lung and impairing immune function of pulmonary CD8+ T cells. C24:4 (n‐6) induces nuclear import of PPARα in pneumal CD8+ T cells, which regulates the transcription of Cpt1a, Dgat1, Cd36, and Fabp1, leading to the activation of fatty acid oxidation (FAO). The robust FAO results in suppression of CD8+ T cells. Genetically depleting PPARα in mice, pharmacologically inhibiting C24:4 (n‐6)‐induced PPARα in the nucleus or directly suppressing PPARα activity effectively attenuates PLA2G16‐C24:4 (n‐6) axis‐based immune dysfunction of CD8+ T cells and their according anti‐tumor activities. These results imply that PLA2G16‐mediated C24:4 (n‐6) accumulation in the lung acts as a metabolic disorder to CD8+ T cell antitumor activity and highlights a critical role of PLA2G16 in promoting TNBC lung metastasis. Targeting PLA2G16 and combination with anti‐PD‐1‐based immunotherapy may be an effective strategy for clinical tumor immunotherapy.

Illustrating how tumor‐derived PLA2G16 regulates tetracosatetraenoic acid (C24:4 (n‐6)) accumulation and CD8+ T cell activation via the C24:4‐PPARα‐FAO axis in early metastatic niches, thereby promoting lung metastasis of triple‐negative breast cancer.