Abstract 5216: RPS19-C5AR1 axis in tumor-associated macrophages drives glioblastoma progression: Insights from single-cell transcriptomics
Authors: Chan-Chuan Liu, Gangga Anuraga, Cheng-Lin Wu, Jian-Ying Chuang, Chih-Yang Wang, Pin-Yuan Chen, Kwang-Yu Chang
Journal: Cancer Research (2025)

Glioblastoma (GBM) is a prevalent and lethal disease with limited treatment options. Tumor-associated macrophages (TAMs), which comprise up to 30% of the GBM mass, play a pivotal role in shaping the TME by supporting tumor growth and establishing an immunosuppressive and inflammatory environment. To investigate how tumor cells affect TAMs during TME evolution, we analyzed single-cell transcriptomics (SCT) datasets from GBM patient-derived tumor mass (Core) and peri-tumoral adjacent tissues (Margin), alongside murine datasets from healthy and GL261-bearing brains. This comparison aimed to clarify the immunological landscapes of GBM and identify specific interactions between tumor cells and TAMs. Margin SCT data revealed increased cellular heterogeneity compared to the Core, with immune cells, tumor cells, and brain stromal cells contributing 57%, 3%, and 40% of the total cell population, respectively. UCell analysis of GBM subtype signatures demonstrated a strong association between TAMs in the Margin and mesenchymal signatures, which are linked to poor prognosis. Further reclustering of TAMs in Margin and the comparison with murine SCT datasets showed that these cells were predominantly derived from peripheral monocytes and macrophages, with M1-like TAMs representing the majority. Pseudotime trajectory analysis revealed that M1-like TAMs serve as precursors to protumoral M2 TAMs. Cell-cell communication mediated by ligand-receptor interactions among tumor cells, TAMs, T cells, and NK cells identified a critical interaction between tumor-derived ribosomal protein S19 (RPS19) and C5AR1 on TAMs. C5AR1 was highly expressed in M1-like TAMs across patient and murine datasets, while RPS19 was ubiquitously expressed by all cell types. In vitro models confirmed that M1 macrophages and microglia exhibited higher C5AR1 expression than their M2 counterparts. Analysis of public datasets (The Cancer Genome Atlas-GBM and Chinese Glioma Genome Atlas) showed elevated C5AR1 expression in GBM tissues, particularly in recurrent tumors, and a strong correlation between high C5AR1 expression and poor patient survival. Additionally, tumor-derived RPS19 was released extracellularly under growth stress or therapeutic interventions, promoting an inflammatory TME through M1 TAM polarization and driving GBM progression. These findings suggest that targeting the RPS19-C5AR1 axis, in combination with current therapies, may represent a promising strategy to improve GBM outcomes. Citation Format: Chan-Chuan Liu, Gangga Anuraga, Cheng-Lin Wu, Jian-Ying Chuang, Chih-Yang Wang, Pin-Yuan Chen, Kwang-Yu Chang. RPS19-C5AR1 axis in tumor-associated macrophages drives glioblastoma progression: Insights from single-cell transcriptomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5216.