Evidence map›Paper›PMID 41316300›Full record

ArticleJournal of translational medicine2025

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

Fansheng Meng, Fulin Nian, Haokang Feng, Zhixue Chen, Qiuyu Jiang, Feng Zhang, Lin Xu, Yueying Chen, Hao Zhang, Tao Ye and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Review
  3. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Fansheng Meng *Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
Fulin Nian *Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Haokang Feng *Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Zhixue ChenDepartment of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Qiuyu JiangDepartment of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Feng ZhangDepartment of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Lin XuDepartment of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Yueying ChenDepartment of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Hao ZhangDepartment of Oncology, Minhang Branch, Zhongshan Hospital, Fudan University, No. 170, Shensong Road, Shanghai, 200032, China.
Tao YeDepartment of Oncology, Minhang Branch, Zhongshan Hospital, Fudan University, No. 170, Shensong Road, Shanghai, 200032, China. ye_tao@fudan.edu.cn.
Biwei YangLiver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. yang.biwei@zs-hospital.sh.cn.

Funding

Shanghai Sailing Program 24YF2704900
6 · The paper itself

Abstract

backgroundsHepatocellular 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.

methodsBulk 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.

resultsHigh 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), recurrence-free 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 secreted CXCL2, recruiting CD56dimCD16highNR4A3high cytotoxic NK cells, enhancing tumor cell apoptosis and improving prognosis. In patients receiving PD-1 therapy, those with high infiltration of SGMS2+ macrophages and CD56dimCD16highNR4A3high NK cells demonstrated superior treatment responsiveness and prolonged survival.

conclusionsSGMS2 could polarize macrophages toward the M1 phenotype. SGMS2+ macrophages secrete CXCL2 to recruit CD56dimCD16highNR4A3high NK cells, thereby enhancing tumor apoptosis. High infiltration of SGMS2+ macrophages and CD56dimCD16highNR4A3high NK cells correlates with superior PD-1 therapy responsiveness and extended survival.

Indexed as

Carcinoma, HepatocellularKiller Cells, NaturalLiver NeoplasmsMacrophagesProgrammed Cell Death 1 ReceptorApoptosisCell Line, TumorFemaleHumansMalePrognosisTreatment OutcomeTumor MicroenvironmentProgrammed Cell Death 1 ReceptorHepatocellular carcinomaImmune checkpoint inhibitorsMacrophageNatural killer cellSphingomyelin synthase 2Tumor microenvironment

Identifiers

PMID41316300
PMCPMC12763894

What OpenQuestion holds

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LicenceCC BY-NC-ND
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.