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Background <p>Diffuse large B-cell lymphoma (DLBCL) is biologically heterogeneous and is associated with variable clinical outcomes. We aimed to develop a tumor-associated macrophage (TAM)-related ferroptosis–glycolysis prognostic signature and to explore selected signature genes in preclinical models.</p> Methods <p>This retrospective multi-cohort computational prognostic biomarker-development study integrated public single-cell and bulk transcriptomic datasets. GSE10846 was used for feature selection, model fitting, and parameter tuning, whereas GSE32918, GSE69051, and TCGA-DLBC were used as model-selection validation cohorts. Exploratory immune, genomic, and computational drug-sensitivity analyses were performed. Signature-gene expression was assessed in 27 archived DLBCL tissues, and GCLC and SLC1A5 were further examined in TAM-related preclinical models in vitro and in vivo.</p> Results <p>An 11-gene TAM-related ferroptosis–glycolysis signature (TAMFGS) was developed. The time-dependent AUCs (95% CIs) were 0.978 (0.966–0.990), 0.986 (0.976–0.995), and 0.982 (0.966–0.999) at 1, 3, and 5&#xa0;years, respectively, in GSE10846; 0.622 (0.524–0.720), 0.608 (0.515–0.702), and 0.619 (0.524–0.715) in GSE32918; 0.516 (0.286–0.747), 0.741 (0.548–0.934), and 0.754 (0.516–0.993) at 1, 2, and 3&#xa0;years, respectively, in GSE69051; and 0.929 (0.850–1.000), 0.674 (0.382–0.966), and 0.677 (0.402–0.952) at 1, 3, and 5&#xa0;years, respectively, in TCGA-DLBC. In GSE10846, the continuous TAMFGS score remained associated with overall survival after adjustment for available covariates (HR, 1.094; 95% CI, 1.082–1.106; <i>p</i> &lt; 0.001). Exploratory analyses identified associations between TAMFGS and immune-related transcriptomic estimates and computationally predicted drug sensitivity. GCLC or SLC1A5 knockdown was associated with ferroptosis-associated molecular changes and an M1-like inflammatory shift in the THP-1-derived TAM model and was associated with reduced DLBCL growth in preclinical models.</p> Conclusion <p>In retrospective transcriptomic DLBCL cohorts, TAMFGS was associated with overall survival. GCLC and SLC1A5 emerged as TAM-related candidate genes that warrant further mechanistic and prospective validation.</p> Graphical Abstract <p></p>

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Transcriptomic development of a tumor-associated macrophage ferroptosis-glycolysis prognostic signature in diffuse large B-cell lymphoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Yingjun Wang,
  • Lai Wei,
  • Jieting Wang,
  • Qianqian Liu,
  • Mengqian Zhang,
  • Mingzhi Zhang

摘要

Background

Diffuse large B-cell lymphoma (DLBCL) is biologically heterogeneous and is associated with variable clinical outcomes. We aimed to develop a tumor-associated macrophage (TAM)-related ferroptosis–glycolysis prognostic signature and to explore selected signature genes in preclinical models.

Methods

This retrospective multi-cohort computational prognostic biomarker-development study integrated public single-cell and bulk transcriptomic datasets. GSE10846 was used for feature selection, model fitting, and parameter tuning, whereas GSE32918, GSE69051, and TCGA-DLBC were used as model-selection validation cohorts. Exploratory immune, genomic, and computational drug-sensitivity analyses were performed. Signature-gene expression was assessed in 27 archived DLBCL tissues, and GCLC and SLC1A5 were further examined in TAM-related preclinical models in vitro and in vivo.

Results

An 11-gene TAM-related ferroptosis–glycolysis signature (TAMFGS) was developed. The time-dependent AUCs (95% CIs) were 0.978 (0.966–0.990), 0.986 (0.976–0.995), and 0.982 (0.966–0.999) at 1, 3, and 5 years, respectively, in GSE10846; 0.622 (0.524–0.720), 0.608 (0.515–0.702), and 0.619 (0.524–0.715) in GSE32918; 0.516 (0.286–0.747), 0.741 (0.548–0.934), and 0.754 (0.516–0.993) at 1, 2, and 3 years, respectively, in GSE69051; and 0.929 (0.850–1.000), 0.674 (0.382–0.966), and 0.677 (0.402–0.952) at 1, 3, and 5 years, respectively, in TCGA-DLBC. In GSE10846, the continuous TAMFGS score remained associated with overall survival after adjustment for available covariates (HR, 1.094; 95% CI, 1.082–1.106; p < 0.001). Exploratory analyses identified associations between TAMFGS and immune-related transcriptomic estimates and computationally predicted drug sensitivity. GCLC or SLC1A5 knockdown was associated with ferroptosis-associated molecular changes and an M1-like inflammatory shift in the THP-1-derived TAM model and was associated with reduced DLBCL growth in preclinical models.

Conclusion

In retrospective transcriptomic DLBCL cohorts, TAMFGS was associated with overall survival. GCLC and SLC1A5 emerged as TAM-related candidate genes that warrant further mechanistic and prospective validation.

Graphical Abstract