Single-Cell Profiling Reveals Immune-Based Mechanisms Underlying Tumor Radiosensitization by a Novel Mn Porphyrin
Sun Up Noh1,2, Jinyeong Lim3,4, Sung-Won Shin1
1Department of Radiation Oncology, Samsung Medical Center, Seoul 06351, Republic of Korea.
Abstract:
Manganese porphyrins reportedly exhibit synergic effects when combined with irradiation. However, an in-depth understanding of intratumoral heterogeneity and immune pathways, as affected by Mn porphyrins, remains limited. Here, we explored the mechanisms underlying immunomodulation of a clinical candidate, MnTnBuOE-2-PyP5+ (BMX-001, MnBuOE), using single-cell analysis in a murine carcinoma model. Mice bearing 4T1 tumors were divided into four groups: control, MnBuOE, radiotherapy (RT), and combined MnBuOE and radiotherapy (MnBuOE/RT). In epithelial cells, the epithelial-mesenchymal transition, TNF-α signaling via NF-кB, angiogenesis, and hypoxia-related genes were significantly downregulated in the MnBuOE/RT group compared with the RT group. All subtypes of cancer-associated fibroblasts (CAFs) were clearly reduced in MnBuOE and MnBuOE/RT. Inhibitory receptor-ligand interactions, in which epithelial cells and CAFs interacted with CD8+ T cells, were significantly lower in the MnBuOE/RT group than in the RT group. Trajectory analysis showed that dendritic cells maturation-associated markers were increased in MnBuOE/RT. M1 macrophages were significantly increased in the MnBuOE/RT group compared with the RT group, whereas myeloid-derived suppressor cells were decreased. CellChat analysis showed that the number of cell-cell communications was the lowest in the MnBuOE/RT group. Our study is the first to provide evidence for the combined radiotherapy with a novel Mn porphyrin clinical candidate, BMX-001, from the perspective of each cell type within the tumor microenvironment.
Insights
This study reveals that combining manganese porphyrin BMX-001 with radiotherapy modulates the tumor microenvironment by reducing cancer-associated fibroblasts and enhancing anti-tumor immunity. This combination therapy shows promise for cancer treatment.
Area of Science:
- Cancer Research
- Immunology
- Pharmacology
Background:
- Manganese porphyrins (Mn porphyrins) show synergistic effects with irradiation, but their impact on intratumoral heterogeneity and immune pathways is not fully understood.
- A clinical candidate, MnTnBuOE-2-PyP5+ (BMX-001), is being investigated for its therapeutic potential.
Purpose of the Study:
- To explore the immunomodulatory mechanisms of BMX-001 in combination with radiotherapy (RT) within the tumor microenvironment.
- To investigate the effects on epithelial cells, cancer-associated fibroblasts (CAFs), and immune cell populations using single-cell analysis.
Main Methods:
- Single-cell analysis was performed on murine 4T1 carcinoma models.
- Mice were treated with control, BMX-001, RT, or combined BMX-001/RT.
- Gene expression, cell-cell interactions (CellChat), and cell type abundance were analyzed.
Main Results:
- Combined BMX-001/RT downregulated epithelial-mesenchymal transition, TNF-α signaling, angiogenesis, and hypoxia genes.
- BMX-001/RT significantly reduced all CAF subtypes and inhibitory receptor-ligand interactions with CD8+ T cells.
- The combination therapy increased dendritic cell maturation markers and M1 macrophages while decreasing myeloid-derived suppressor cells, leading to reduced overall cell-cell communication.
Conclusions:
- The combination of BMX-001 and RT effectively reprograms the tumor microenvironment, suppressing pro-tumorigenic pathways and enhancing anti-tumor immunity.
- This study provides the first single-cell perspective on the combined effects of BMX-001 and RT, highlighting its potential as a novel cancer therapy.
