Rbfox3 Promotes Transformation of MDSC-Like Tumor Cells to Shape Immunosuppressive Microenvironment

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) promote tumor progression via immunosuppression.
• Bacterial lipopolysaccharides (LPS) are found in solid tumors and implicated in malignant progression, but mechanisms remain unclear.

Purpose of the Study:

• To investigate the mechanism by which LPS promotes tumor malignant progression.
• To identify novel therapeutic targets for enhancing anti-tumor immunity.

Main Methods:

• Induction of MDSC-like tumor cells (MLTCs) using low-dose, long-term LPS stimulation.
• CRISPR-Cas9 activity screening to identify key proteins in MLTC formation.
• Analysis of Rbfox3's role in regulating Ass1 expression via phase-separated particles.
• Evaluation of crocin's effect on MLTCs and its synergy with immune checkpoint inhibitors (ICIs).

Main Results:

• A novel cell type, MLTCs, was identified, expressing both tumor and MDSC markers.
• MLTCs exhibit immunosuppressive functions, inhibit NK and T cell activity, and promote tumor proliferation and vasculogenic mimicry.
• CRISPR screening identified Rbfox3 as essential for LPS-induced MLTC formation.
• Rbfox3 regulates Ass1 expression through phase-separated particles; crocin disrupts these particles, inhibiting MLTC generation.

Conclusions:

• LPS can induce MLTCs that contribute to tumor progression and immunosuppression.
• Rbfox3 is a key regulator of MLTC formation, acting via phase-separated particles to control Ass1 expression.
• Crocin shows potential as a therapeutic agent to inhibit MLTCs and enhance the efficacy of ICIs in cancer treatment.