A dual-targeting peptide-drug conjugate based on CXCR4 and FOLR1 inhibits triple-negative breast cancer

Area of Science:

• Oncology
• Immunology
• Drug Development

Background:

• Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to low marker expression and an immunosuppressive tumor microenvironment.
• Current treatments for TNBC are limited, necessitating novel therapeutic strategies.

Purpose of the Study:

• To develop and evaluate a dual-targeting peptide-drug conjugate (PDC) for enhanced TNBC inhibition.
• To investigate the PDC's ability to selectively deliver cytotoxic agents and modulate the tumor immune microenvironment.

Main Methods:

• A dual-targeting PDC was designed to deliver Monomethyl Auristatin E (MMAE) by targeting C-X-C chemokine receptor type 4 (CXCR4) and folate receptor 1 (FOLR1).
• Antitumor activity was assessed in vitro using human cell lines and in vivo using murine transplanted tumor models.
• The impact of the PDC on the tumor immune microenvironment was analyzed, including T cell infiltration and myeloid-derived suppressor cell populations.

Main Results:

• The dual-targeting PDC demonstrated potent and selective delivery of MMAE into tumor cells, leading to synergistic growth and metastasis inhibition.
• Effective antitumor activity was observed in various preclinical models with no apparent toxicity.
• Combination therapy with the dual-targeting PDC and radiotherapy significantly modulated the immunosuppressive tumor microenvironment, increasing CD8+ T cell infiltration and reducing suppressive immune cells.

Conclusions:

• The dual-targeting PDC is a promising therapeutic strategy for TNBC, offering potent antitumor effects.
• This approach effectively rebalances the tumor immune microenvironment, promoting tumor regression.
• Further clinical investigation of this dual-targeting PDC for cancer therapy is warranted.