Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide, and its progression is closely linked to the establishment of an immunosuppressive tumor microenvironment. Myristoylated alanine-rich C kinase substrate (MARCKS) has been implicated in tumor biology; however, its role in regulating immune interactions in HCC remains poorly defined. Here, we performed an integrated multi-omics analysis combining bulk transcriptomics, single-cell RNA sequencing, and spatial transcriptomics to systematically investigate the expression pattern and functional relevance of MARCKS in HCC. We found that MARCKS was significantly upregulated in HCC tissues and that high MARCKS expression was associated with aggressive clinicopathological features and unfavorable prognosis. Single-cell and spatial analyses revealed that MARCKS expression was enriched in myeloid cell populations within the tumor microenvironment. Functional annotation and mIF(Multiple immunofluorescence) validation demonstrated that MARCKS expression was associated with enhanced JAK/STAT3 signaling and M2-like macrophage polarization. Consistently, MARCKS silencing in HCC cell lines reduced STAT3 phosphorylation, suppressed malignant phenotypes in vitro, inhibited tumor growth in vivo, and diminished the capacity of tumor-derived conditioned media to promote macrophage M2 polarization. Together, these findings identify MARCKS as a key regulator of the immunosuppressive tumor microenvironment in HCC and highlight its potential as a therapeutic target for overcoming immune evasion.
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Data availability
RNA-seq raw count data, clinical information, and somatic mutation (MAF) files for HCC were obtained from the TCGA-LIHC cohort via the Genomic Data Commons (https://portal.gdc.cancer.gov/projects/TCGA-LIHC; dbGaP: phs000178). Pan-cancer RNA-seq data integrating TCGA and GTEx were retrieved from the UCSC Xena Toil recompute dataset (https://xenabrowser.net/). The single-cell RNA-seq dataset GSE149614 was downloaded from GEO (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE149614), and the spatial transcriptomics dataset HRA000437 was obtained from NGDC (https://ngdc.cncb.ac.cn/gsa-human/browse/HRA000437).
Code availability
The custom scripts and codes used for data processing and analysis are available from the corresponding author upon reasonable request.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 82360465,82560579); Guangxi Natural Science Foundation (2024GXNSFDA010029, 2025GXNSFAA069704); Guangxi Key Laboratory of Longevity Science and Technology (Open Fund Project No.gxkllst-20241003; Guangxi Science and Technology Program under Grant No.AD25069077; the Special Fund for Clinical Discipline Construction of Guangxi Medical University (GXMULJZ202402); Innovation Project of Guangxi Graduate Education (No. YCSW2025252); The Guangxi Natural Science Foundation Youth Science Fund Project (2025GXNSFBA069037); Young and Middle-aged Scientific Research Capacity Enhancement Project (2024KY0128) and National Postdoctoral Researcher Funding Program (GZC20230583); The Open Project of Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer (GXEKL202401); Youth Science Foundation of Guangxi Medical University (GXMUYSF202501).
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Haifei Qin, Qinchen Lu, and Baicheng Hu contributed equally to this work. Haifei Qin, Qinchen Lu, and Baicheng Hu designed and performed most of the experiments and analyses. Chenlu Lan, Honglong Lu, Donghua Gao, Chongjiu Qin, and Kai Peng assisted with data collection, bioinformatics analysis, and figure preparation. Xin Zhou, Yongguang Wei, Xiwen Liao, and Tao Peng provided technical support and contributed to data interpretation. Tao Peng, Liming Shang, and Guangzhi Zhu supervised the project, critically revised the manuscript for important intellectual content, and served as corresponding authors. All authors read and approved the final manuscript.
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Qin, H., Lu, Q., Hu, B. et al. Integrated multi-omics analysis reveals that MARCKS reprograms the immunosuppressive microenvironment to drive hepatocellular carcinoma progression. npj Precis. Onc. (2026). https://doi.org/10.1038/s41698-026-01372-7
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DOI: https://doi.org/10.1038/s41698-026-01372-7
