# Tumor Cell‐Derived CXCL2 Potentiates Neutrophil‐Mediated Antitumor Immunity by Inhibiting Cholesterol Biosynthesis in Hepatocellular Carcinoma

## TL;DR

This study shows that CXCL2, a protein reduced in liver cancer, helps fight tumors by changing immune cells and reducing cholesterol production.

## Contribution

CXCL2's intracellular role in inhibiting cholesterol biosynthesis and promoting antitumor immunity in HCC is newly revealed.

## Key findings

- Low CXCL2 levels in HCC correlate with poor prognosis and weak response to immunotherapy.
- CXCL2 promotes antitumor neutrophil polarization and suppresses HCC progression.
- CXCL2 inhibits cholesterol biosynthesis by blocking YBX1 and SREBF2 activity.

## Abstract

Hepatocellular carcinoma (HCC) is a major cause of cancer‐related death worldwide. Despite the proven efficacy of immunotherapy against malignancies, a large proportion of patients with HCC fail to benefit from these efficacious agents because of their overwhelmingly immunosuppressive microenvironment. Therefore, there is an urgent need to identify key genes and develop effective strategies for reshaping the HCC microenvironment. Here, a significant downregulation of C‐X‐C motif chemokine ligand 2 (CXCL2) in HCC is identified due to gene copy number loss, which correlates with poor prognosis and suboptimal responsiveness to immunotherapy. Subsequently, it is found that CXCL2 can not only recruit neutrophils as expected, but also induce their polarization toward the antitumor type to curb HCC progression. Mechanistically, differing from the prevailing notion that CXCL2 primarily functions extracellularly as a chemokine, it is demonstrated that intracellular CXCL2 can bind to Y‐Box Binding Protein 1 (YBX1) and prevent its nuclear translocation. Consequently, this reduces the transcription of sterol regulatory element binding transcription factor 2 (SREBF2) and suppresses cholesterol biosynthesis, thereby remodeling HCC microenvironment and impeding HCC development. In summary, this study highlights the unconventional role of CXCL2 in regulating neutrophil polarization and immune responses in HCC, positioning it as a potential therapeutic target for HCC.

This study identifies the unconventional role of CXCL2 in regulating neutrophil polarization and immune responses in HCC. Unlike the common view that CXCL2 acts mainly as an extracellular chemokine, intracellular CXCL2 can interact with YBX1 and prevent its nuclear translocation. This reduces SREBF2 transcriptional expression and decreases cholesterol biosynthesis, thereby reshaping the HCC microenvironment and inhibiting HCC progression.