Journal for immunotherapy of cancer · 2026
Non-enzymatic Rnaseh2c orchestrates proliferating macrophage-driven immunosuppression and HCC progression via Cdk9 proliferation axis and CCL2/CCR2-mediated CD8+ Tex infiltration: a novel therapeutic paradigm with "Rnaseh2c-In1" inhibitor.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Wang Zengbin, Xiao Ruiying, Liu Mengxin, Ceng Lihua, Lin Zikun, Zheng Xinyu, Shi Miaoxin, Ye Hong, Wu Linqing, Tang Nanhong
Аннотация
BACKGROUND: Tumor-associated macrophages are pivotal drivers of hepatocellular carcinoma (HCC) progression. However, the functional contributions of proliferating macrophages (Prolif Ms) within the tumor microenvironment (TME) remain poorly defined.
METHODS: Here, we integrated single-cell RNA sequencing, Cleavage Under Targets and Tagmentation (CUT&Tag), bulk RNA sequencing, multiparametric immunofluorescence, flow cytometry, and molecular dynamics simulation to dissect the phenotype, functional landscape, and targeting strategy of Prolif Ms in HCC.
RESULTS: We identified a novel Prolif Ms subset characterized by high expression of proliferation markers (Cdk1, Mki67), distinct from classical M1/M2 macrophages. Mechanistically, ribonuclease H2 subunit C (Rnaseh2c) acts as a non-enzymatic regulator, binding directly to the cyclin-dependent kinase promoter to drive macrophage proliferation while suppressing endocytic and antigen-presenting capabilities. Rnaseh2c further promotes CD8+ exhausted T cell (CD8+ Tex) infiltration via the C-C motif chemokine ligand 2/C-C motif chemokine receptor type 2 (CCL2/CCR2) axis, fostering an immunosuppressive TME. Notably, Rnaseh2c exhibits cancer-promoting effects in both macrophages and hepatocytes. We developed a specific inhibitor "Rnaseh2c-In1", which inhibits HCC growth by reducing CCL2 secretion and CD8+ Tex infiltration, demonstrating favorable pharmacokinetics and low toxicity.
CONCLUSIONS: This study elucidates a non-enzymatic Rnaseh2c-driven mechanism regulating Prolif Ms, providing a novel therapeutic target and candidate compound for HCC treatment.
METHODS: Here, we integrated single-cell RNA sequencing, Cleavage Under Targets and Tagmentation (CUT&Tag), bulk RNA sequencing, multiparametric immunofluorescence, flow cytometry, and molecular dynamics simulation to dissect the phenotype, functional landscape, and targeting strategy of Prolif Ms in HCC.
RESULTS: We identified a novel Prolif Ms subset characterized by high expression of proliferation markers (Cdk1, Mki67), distinct from classical M1/M2 macrophages. Mechanistically, ribonuclease H2 subunit C (Rnaseh2c) acts as a non-enzymatic regulator, binding directly to the cyclin-dependent kinase promoter to drive macrophage proliferation while suppressing endocytic and antigen-presenting capabilities. Rnaseh2c further promotes CD8+ exhausted T cell (CD8+ Tex) infiltration via the C-C motif chemokine ligand 2/C-C motif chemokine receptor type 2 (CCL2/CCR2) axis, fostering an immunosuppressive TME. Notably, Rnaseh2c exhibits cancer-promoting effects in both macrophages and hepatocytes. We developed a specific inhibitor "Rnaseh2c-In1", which inhibits HCC growth by reducing CCL2 secretion and CD8+ Tex infiltration, demonstrating favorable pharmacokinetics and low toxicity.
CONCLUSIONS: This study elucidates a non-enzymatic Rnaseh2c-driven mechanism regulating Prolif Ms, providing a novel therapeutic target and candidate compound for HCC treatment.