In situ generation of copper complex and multivalent CXCR4 inhibitor via ROS-responsive nanoplatform suppresses breast cancer metastasis

Metastasis remains the principal driver of breast cancer mortality, a complex process shaped by two key hallmarks: an immunosuppressive tumor microenvironment that facilitates pre-metastatic niche formation and the persistent activation of the pro-metastatic CXCL12–CXCR4 chemokine axis. To simultaneously blockade these drivers, we developed a multifunctional, H 2 O 2 -responsive nanoplatform composed of self-assembled HA-AMD-Cu and the prodrug CBD. This innovative system leverages competitive coordination chemistry to achieve the precise in situ generation of therapeutics specifically within the tumor site. Under the elevated H 2 O 2 levels characteristic of the tumor microenvironment, CBD releases diethyldithiocarbamate (DTC), which effectively competes for Cu 2+ from the HA-AMD-Cu complex. This reaction generates cytotoxic Cu(DTC) 2 while liberating the active multivalent CXCR4 antagonist, HA-AMD. Consequently, Cu(DTC) 2 exerts potent tumor-selective cytotoxicity and induces robust immunogenic cell death (ICD) to reactivate suppressed anti-tumor immunity, while HA-AMD simultaneously inhibits CXCL12-driven metastatic spread. This precise “off-to-on” switch demonstrated significant therapeutic efficacy against both primary tumors and lung metastases in aggressive breast cancer models. Collectively, integrating multivalent CXCR4 blockade with tumor-selective ICD induction provides a promising, targeted strategy for combating metastatic breast cancer.