SPP1+ Macrophages Promote Immunosuppression in Post-TACE Hepatocellular Carcinoma Involving Lactate-Induced Lactylation and Potential SPP1-CD44 Signaling.

Authors

Hongyu Wang, Guojun Liang, Ting Liu, Min He, Yang Jiang, Jinwei Li, Yushu Ouyang, Shufang Hao, Wendao Liu, Jiaping Li

Published in

Journal of hepatocellular carcinoma. Volume 13. Pages 603485. Epub Jul 08, 2026.

Abstract

Transarterial chemoembolization (TACE) treats inoperable liver cancer by inducing tumor ischemia, but subsequent hypoxia can promote an immunosuppressive microenvironment. This study explores how TACE-related hypoxia influences immune cells through lactate metabolism and lactylation.
Single-cell RNA sequencing of TACE-treated and newly diagnosed liver cancer samples was performed. Scores were assigned to lactate-related gene sets, and differentially expressed genes were identified. Bioinformatics analysis integrated scRNA-seq, TCGA, and GEO data. Machine learning derived a consensus gene signature, and a prognostic nomogram was constructed. The study evaluated immune infiltration and drug sensitivity. Key findings were validated via spatial transcriptomics, in vitro experiments, and immunofluorescence.
We identified seven distinct single-cell types, noting an increase in macrophage infiltration and a decrease in CD8+ T cells within the TACE group. A six-gene consensus signature related to lactate-comprising SPP1, DNASE1L3, HRG, TPX2, LAPTM4B, and G6PD-was identified and found to be significantly associated with poor prognosis. This consensus gene score and T, N staging constructed a prognostic nomogram validated by calibration curves and decision curves. We also found that SPP1+ macrophages were elevated in the TACE treatment group, with increased lactate-related gene set scores, and were associated with hypoxia, glycolysis, and inflammatory pathways. Cell communication analysis suggested a potential regulatory link between SPP1+ macrophages and CD8+ T cells, highlighting the potential involvement of the SPP1-CD44 axis. Cell experiments showed that hypoxic, lactate-rich environments lead to macrophage lactylation, increasing SPP1+ macrophages and decreasing CD8+ IFN-γ+ T cells. Spatial transcriptomics and immunofluorescence staining revealed co-localization of SPP1+ macrophages with CD8+ T cells.
We established a lactate-associated six-gene signature and prognostic nomogram. The immunosuppressive microenvironment following TACE in liver cancer is highly correlated with the activation of lactate-related genes and an increase in SPP1+ macrophages. These macrophages are closely associated with CD8+ T cells dysfunction, with the SPP1-CD44 pathway serving as a candidate narrative for this intercellular crosstalk. These findings suggest that targeting lactate-induced lactylation or the potential SPP1-CD44 interaction may offer promising therapeutic opportunities to counteract immune evasion after TACE therapy.

PMID:
42438784
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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