SGMS2+ macrophages enhance NR4A3hi - NK cell infiltration to improve prognosis and PD-1 treatment efficacy in hepatocellular carcinoma

Sep 28, 2026

Hepatocellular carcinoma develops within an immunosuppressive tumor microenvironment that drives malignant progression. This study focuses on sphingomyelin synthase 2 (SGMS2), a key sphingolipid metabolism enzyme, and tests how SGMS2 shapes tumor immunity and patient outcomes. Using bulk RNA-seq, single-cell RNA-seq, spatial transcriptomics, and multiplex immunofluorescence, the research links SGMS2 expression to macrophage polarization and NK cell recruitment. SGMS2+ macrophages promote an M1-like phenotype, secrete CXCL2, increase CD56dimCD16highNR4A3high NK infiltration, enhance tumor apoptosis, and correlate with improved prognosis and superior PD-1 therapy responsiveness.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Background

Methods

Results

SGMS2 expression and prognosis

Macrophage polarization and immune cell recruitment

PD-1 therapy responsiveness

Conclusions

Keywords

Introduction

Meng et al. Journal of Translational Medicine (2026) 24:13 [https://doi.org/10.1186/s12967-025-07040-x](https://doi.org/10.1186/s12967-025-07040-x) Journal of Translational Medicine RESEARCH Open Access SGMS2+ macrophages enhance NR4A3hi NK cell infiltration to improve prognosis and PD-1 treatment efficacy in hepatocellular carcinoma Fansheng Meng 1†, Fulin Nian2†, Haokang Feng3†, Zhixue Chen2, Qiuyu Jiang2, Feng Zhang2, Lin Xu2, Yueying Chen2, Hao Zhang4, Tao Ye4* and Biwei Yang 1* Abstract Backgrounds Hepatocellular carcinoma (HCC) is characterized by an immunosuppressive tumor microenvironment (TME) that critically propels malignant evolution. Sphingomyelin synthase 2 (SGMS2), the pivotal sphingolipid metabolizing enzyme, catalyzes the conversion of ceramide to sphingomyelin. Emerging evidence highlights sphingolipid metabolism as a key regulator of tumor immunity, particularly in shaping macrophage phenotypes within the TME. However, the macrophage-specific contributions of SGMS2 to HCC progression remain unexplored. This study elucidates the critical role of SGMS2 in shaping TME and influencing patient prognosis. Methods Bulk RNA-seq analysis was performed using TCGA-LIHC datasets (n = 371) . Single-cell RNA sequencing and spatial transcriptomics were used to identify SGMS2-expressing cell types and evaluate spatial immune interactions. Clinical validation was performed on a cohort of 188 HCC patients (2017–2022) using multiplex immunofluorescence to quantify SGMS2+ macrophages and NR4A3hi NK cells. THP-1 monocytes were transfected with lentiviral SGMS2 overexpression vectors and differentiated into macrophages via PMA induction. Co-culture assays with liver tumor cells were performed in transwell plates for 48 h, followed by tumor cell apoptosis assessment using Annexin V-FITC/ PI staining and flow cytometry. Results High SGMS2 expression in HCC tissues was associated with improved patient prognosis. SGMS2 was mainly expressed in macrophages within the HCC immune microenvironment, promoting their polarization toward the M1-like phenotype. High infiltration of SGMS2+ macrophages significantly prolonged overall survival (OS), recurrencefree survival (RFS), and early RFS. Notably, patients with high infiltration of SGMS2+ macrophages accompanied by low infiltration of SGMS2-macrophages had the most favorable prognosis. Mechanistically, SGMS2+ macrophages †Fansheng Meng, Fulin Nian, and Haokang Feng have contributed equally to this work. *Correspondence: Tao Ye[ye_tao@fudan.edu.cn](ye_tao@fudan.edu.cn)[ ](ye_tao@fudan.edu.cn)Biwei Yang [yang.biwei@zs-hospital.sh.cn](yang.biwei@zs-hospital.sh.cn) Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/l](vecommons.org/l)icenses/by-nc-nd/4.0/. Meng et al. Journal of Translational Medicine (2026) 24:13 Page 2 of 17 secreted CXCL2, recruiting CD56dimCD16highNR4A3high cytotoxic NK cells, enhancing tumor cell apopt

FAQs

What is the main role of SGMS2 in hepatocellular carcinoma described here?

SGMS2 shapes the tumor microenvironment by influencing macrophage phenotypes and immune interactions, which affects patient prognosis and PD-1 treatment efficacy.

How were SGMS2-expressing cells and immune interactions identified?

Bulk RNA-seq, single-cell RNA sequencing, and spatial transcriptomics were used to determine SGMS2-expressing cell types and evaluate spatial immune interactions.

What mechanism links SGMS2+ macrophages to improved outcomes?

SGMS2+ macrophages polarize toward an M1-like phenotype and secrete CXCL2 to recruit CD56dimCD16highNR4A3high cytotoxic NK cells, enhancing tumor cell apoptosis and survival.

Sep 28, 2026

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