Optical controlled and nuclear targeted CECR2 competitor to downregulate CSF-1 for metastatic breast cancer...

Area of Science:

• Oncology
• Immunology
• Drug Discovery

Background:

• Tumor-associated macrophages (TAMs) promote breast cancer progression and immunosuppression through crosstalk with cancer cells.
• Cat eye syndrome chromosome region candidate 2 (CECR2) is overexpressed in breast cancer and activates nuclear factor κB (NF-κB) signaling, leading to colony-stimulating factor-1 (CSF-1) release.
• Inhibiting CECR2 can downregulate CSF-1 and reduce M2-type TAMs, which are associated with tumor growth.

Purpose of the Study:

• To develop a novel therapeutic strategy targeting the CECR2-NF-κB pathway to overcome immunosuppression in metastatic breast cancer.
• To construct and evaluate a chimeric peptide-based, optically controlled CECR2 competitor (N-PB) for enhanced drug delivery and immunogenic cell death induction.

Main Methods:

• Identification of CECR2 overexpression in breast cancer and its role in activating NF-κB signaling.
• Development of N-PB, an optically controlled CECR2 inhibitor, for targeted delivery and therapeutic effect.
• In vivo evaluation of N-PB's efficacy in targeting breast cancer, suppressing primary tumors, and modulating TAMs under optical irradiation.

Main Results:

• N-PB demonstrated favorable breast cancer targeting and primary tumor suppression under optical irradiation.
• N-PB competitively inhibited CECR2 and NF-κB(RelA) interactions, downregulating CSF-1 and reducing immunosuppressive M2-like TAMs.
• The treatment shifted TAMs towards an antitumorigenic M1-like phenotype and activated systemic anti-tumor immunity.

Conclusions:

• Interrupting the CECR2-mediated crosstalk between breast cancer cells and TAMs is a viable therapeutic strategy.
• Optically controlled N-PB offers a promising approach for metastatic breast cancer treatment by modulating the tumor microenvironment and enhancing anti-tumor immunity.