Cuproptosis-inducing photothermal nanotherapy coupled with ECM destabilization drives potent tumor regression and immune reawakening

Major challenges are posed by the dense extracellular matrix and immunosuppressive tumor microenvironment in the treatment of aggressive breast cancers such as triple-negative breast cancer. Conventional treatments usually fail to achieve durable outcomes because they poorly address ECM-mediated barriers that facilitate tumor cell migration, driving rapid post-therapy recurrence. We designed a hollow nanocomplex incorporating an extracellular matrix-disrupting agent to improve intratumoral penetration and potentiate immunogenic cell death. The system consisted of hollow copper sulfide nanoparticles loaded with 4-methylumbelliferone, modified with polymetformin, and surface-coated with hyaluronic acid to ensure targeted delivery via CD44 receptors. Upon 1064 nm near-infrared laser irradiation, hollow copper sulfide loaded with 4- methyl umberlliferone and coated with polymetformin and hyaluronic acid generates localized heat for photothermal ablation while releasing 4-MU to inhibit HAS2, disrupting the tumor matrix. Moreover, final group induced immunogenic cell death and downregulated HAS2 and CD44 in vitro along with copper mediated apoptosis. Meanwhile, the final group achieved complete tumor regression in vivo, with no recurrence and full prevention of lung metastasis observed in a 4T1 mouse model. Furthermore, immunostaining confirmed that apoptosis, macrophage repolarization, and immune activation were increased. This research presents a synergistic nanoplatform that integrates matrix remodeling, photothermal therapy (PTT), and immune reprogramming, offering a promising strategy for treating metastatic and immune-evasive breast tumors.