ArticleCell death & disease2022
Heterogeneity induced GZMA-F2R communication inefficient impairs antitumor immunotherapy of PD-1 mAb through JAK2/STAT1 signal suppression in hepatocellular carcinoma.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 48 citations in OpenAlex.
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- Extracellular granzyme K enhances PD-L1 transcription and stability via F2RL1 activation to facilitate tumor immune evasion in lung adenocarcinoma.Journal for immunotherapy of cancer · 2026Article
- Development of a model combining CEUS LI-RADS and clinical features for predicting glypican-3 expression in hepatocellular carcinoma.Abdominal radiology (New York) · 2025Article
- Prognostic significance of key immune cell functional alterations in clear cell renal cell carcinoma.Translational cancer research · 2025Article
- Spatial transcriptomics of glioblastoma defines biologically and clinically significant reprogramming patterns across unique spatial microenvironments.bioRxiv : the preprint server for biology · 2025Article
- Peripheral immune imbalance in pediatric fulminant myocarditis revealed by single-cell sequencing and plasma proteomics.Genes and immunity · 2025Article
- The molecular subtype based on cell cycle-related gene signature predicts the prognosis and chemotherapy and immunotherapy response in gastric cancer.Scientific reports · 2025Article
- Multi-dimensional characterization of cellular states reveals clinically relevant immunological subtypes and therapeutic vulnerabilities in ovarian cancer.Journal of translational medicine · 2025Article
- Comprehensive Analysis of Granzymes and Perforin Family Genes in Multiple Cancers.Biomedicines · 2025Article
- Immune microenvironment spatial landscapes of tertiary lymphoid structures in gastric cancer.BMC medicine · 2025Article
- Coordinated immune networks in leukemia bone marrow microenvironments distinguish response to cellular therapy.Science immunology · 2025Article
- Sclerotic-Type Cutaneous Chronic Graft-Versus-Host Disease Exhibits Activation of T Helper 1 and OX40 Cytokines.The Journal of investigative dermatology · 2024Article
- Article
- Coagulation factor II thrombin receptor as a promising biomarker in breast cancer management.Open life sciences · 2024Article
- Single-cell map of dynamic cellular microenvironment of radiation-induced intestinal injury.Communications biology · 2023Article
- Leveraging a disulfidptosis-related signature to predict the prognosis and immunotherapy effectiveness of cutaneous melanoma based on machine learning.Molecular medicine (Cambridge, Mass.) · 2023Article
- Nucleus-localized circSLC39A5 suppresses hepatocellular carcinoma development by binding to STAT1 to regulate TDG transcription.Cancer science · 2023Article
- New insights into T-cell exhaustion in liver cancer: from mechanism to therapy.Journal of cancer research and clinical oncology · 2023Review
- An 8-gene predicting survival model of hepatocellular carcinoma (HCC) related to pyroptosis and cuproptosis.Hereditas · 2023Article
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Authors and funding
17 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tumor heterogeneity has been associated with immunotherapy and targeted drug resistance in hepatocellular carcinoma (HCC). However, communications between tumor and cytotoxic cells are poorly understood to date. In the present study, thirty-one clusters of cells were discovered in the tumor tissues and adjacent tissues through single-cell sequencing. Moreover, the quantity and function exhaustion of cytotoxic cells was observed to be induced in tumors by the TCR and apoptosis signal pathways. Furthermore, granzyme failure of cytotoxic cells was observed in HCC patients. Importantly, the GZMA secreted by cytotoxic cells was demonstrated to interact with the F2R expressed by the tumor cells both in vivo and in vitro. This interaction induced tumor suppression and T cell-mediated killing of tumor cells via the activation of the JAK2/STAT1 signaling pathway. Mechanistically, the activation of JAK2/STAT1 signaling promoted apoptosis under the mediating effect of the LDPRSFLL motif at the N-terminus of F2R, which interacted with GZMA. In addition, GZMA and F2R were positively correlated with PD-1 and PD-L1 in tumor tissues, while the expressions of F2R and GZMA promoted PD-1 mAb-induced tumor suppression in both mouse model and HCC patients. Finally, in HCC patients, a low expression of GZMA and F2R in the tumor tissues was correlated with aggressive clinicopathological characteristics and poor prognosis. Collectively, GZMA-F2R communication inefficient induces deficient PD-1 mAb therapy and provide a completely novel immunotherapy strategy for tumor suppression in HCC patients.
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