Evidence map›Paper›PMID 39988347›Full record

ArticleJournal for immunotherapy of cancer2025

Targeted delivery of CCL3 reprograms macrophage antigen presentation and enhances the efficacy of immune checkpoint blockade therapy in hepatocellular carcinoma.

Muqi Liu, Linzhe Li, Lu Cao, Wei Li, Xingshi Gu, Min Yang, Di Wu, Yanan Li, Yao Deng, Juan Zhang and 6 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal for immunotherapy of cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.

0numbers the graph read from it
0cells of the map it votes in
18citing 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

18 citing papers in PubMed.

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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

16 authors.

Muqi LiuInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.ORCID http://orcid.org/0009-0007-7631-2798
Linzhe LiInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Lu CaoInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.ORCID http://orcid.org/0000-0002-3602-0340
Wei LiInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Xingshi GuInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Min YangInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Di WuInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Yanan LiInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Yao DengInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Juan ZhangInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Cejun YangInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Qi LiangInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Huaping LiuInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Pengfei RongInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Xiaoqian MaInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China wang_w@csu.edu.cn mxq8933@csu.edu.cn.ORCID http://orcid.org/0000-0002-8315-9927
Wei WangInstitute for Cell Transplantation and Gene Therapy, Third Xiangya Hospital of Central South University, Changsha, Hunan, China wang_w@csu.edu.cn mxq8933@csu.edu.cn.ORCID http://orcid.org/0000-0002-3409-7846

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundHepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide, especially in advanced stages where limited treatment options result in poor prognosis. The immunosuppressive tumor immune microenvironment (TIME), characterized by low immune cell infiltration and exhaustion, limits immunotherapy efficacy. To address this, our study investigates the role of C-C motif chemokine ligand 3 (CCL3) in modulating the HCC TIME.

methodsWe analyzed CCL3 expression in human HCC samples from The Cancer Genome Atlas database, focusing on its correlation with inflammatory gene signatures and immune cell infiltration. High-dimensional single-cell RNA sequencing (scRNA-seq), flow cytometry, and multiplex immunofluorescence were used to investigate CCL3's effects on macrophage function and T cell activation. The biological impact of CCL3 on macrophages was assessed using co-culture systems, confocal imaging, metabolite detection, and inhibition assays. Preclinical HCC models and ex vivo tumor fragment assays further explored how CCL3 modulates immune responses and enhances immune checkpoint blockade efficacy.

resultsOur study shows that CCL3 is suppressed in the tumor microenvironment and positively correlates with immune infiltration and inflammatory responses. Targeted liver delivery of rAAV-Ccl3 reprograms the immune microenvironment in HCC, promoting immune cell recruitment and tertiary lymphoid structure formation, thus suppressing tumor growth via immune engagement. Through scRNA-seq, flow cytometry, and multiplex immunofluorescence, we found that CCL3 enhances macrophage antigen uptake and activates cytotoxic T cells. In vivo and in vitro experiments confirmed that CCL3 facilitates T cell infiltration and upregulates MHC II expression on macrophages, enhancing antigen presentation. The CCL3-CCR5 pathway also boosts macrophage metabolism, increasing lysosomal activity and antigen uptake, thereby strengthening adaptive immune responses and increasing sensitivity to immune checkpoint blockade therapies in preclinical models.

conclusionsThis study highlights the pivotal role of CCL3 in reshaping the TIME and enhancing antitumor immunity in HCC. By promoting immune cell recruitment and enhancing antigen presentation, CCL3 demonstrates significant potential to improve the efficacy of immunotherapy, particularly in combination with immune checkpoint inhibitors. Targeting CCL3 may help to overcome the immunosuppressive TIME in HCC and improve patient outcomes.

Indexed as

Antigen PresentationCarcinoma, HepatocellularChemokine CCL3Immune Checkpoint InhibitorsLiver NeoplasmsMacrophagesAnimalsCell Line, TumorHumansImmunotherapyMiceTumor MicroenvironmentCCL3 protein, humanChemokine CCL3Immune Checkpoint InhibitorsHepatocellular CarcinomaImmunotherapyMacrophagesMajor histocompatibility complex - MHCTumor microenvironment - TME

Identifiers

PMID39988347
PMCPMC11848677

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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.