Orchestrated Cu²⁺-coordinated tetracycline-porphyrin self-assembly remodels tumor microenvironment for photo-enhanced...

Reactive oxygen species (ROS)-based nanodynamic therapy is emerging as a promising approach for tumor treatment, particularly in eliciting immune responses for tumor immunotherapy. Nevertheless, the complex tumor microenvironment (TME) and the constraints of current sensitizers substantially compromise therapeutic efficacy. To address these challenges, we developed a rationally designed nanoplatform (LP/CuTT) through lipoic acid-modified orchestrated Cu²⁺-coordinated tetracycline-porphyrin self-assembly, to precisely remodel the immunosuppressive TME while potentiating antitumor immunotherapy via a novel photo-enhanced chemodynamic therapy (CDT) strategy. In vitro studies demonstrated that LP/CuTT-mediated photo-enhanced CDT effectively promoted concurrent apoptosis and cuproptosis in B16-F10 melanoma cells, coupled with robust induction of immunogenic cell death (ICD). Mechanistic investigations revealed that LP/CuTT drives macrophage polarization from tumor-promoting M2 to antitumor M1 phenotypes while promoting dendritic cell (DC) maturation, thereby orchestrating potent antitumor immune responses. In vivo evaluations showed preferential tumor accumulation of LP/CuTT, correlating with substantial ROS generation at tumor sites and remarkable therapeutic outcomes. Quantitative assessments further demonstrated elevated M1 macrophage infiltration in both tumor and splenic tissues, accompanied by enhanced CD8+ and CD4+ T cell recruitment. These findings provide key insights into developing orchestrated metal-coordinated nanotherapeutics by repurposing existing therapeutic agents, enabling the design of multifunctional systems that integrate efficient chemodynamic activity, TME remodeling, and immune activation for effective nanodynamic therapy.