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Backgrounds <p>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.</p> Methods <p>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&#xa0;transfected with&#xa0;lentiviral SGMS2 overexpression vectors and differentiated into macrophages via PMA induction. Co-culture assays with liver tumor cells were performed in&#xa0;transwell plates&#xa0;for 48&#xa0;h, followed by tumor cell apoptosis assessment using&#xa0;Annexin V-FITC/PI staining and flow cytometry.</p> Results <p>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), 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.</p> Conclusions <p>SGMS2 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • Fansheng Meng,
  • Fulin Nian,
  • Haokang Feng,
  • Zhixue Chen,
  • Qiuyu Jiang,
  • Feng Zhang,
  • Lin Xu,
  • Yueying Chen,
  • Hao Zhang,
  • Tao Ye,
  • Biwei Yang

摘要

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), 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.

Conclusions

SGMS2 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.