Tailoring tumor-associated macrophages (TAMs) into the tumoricidal phenotype represents a high-profile strategy for tumor immunotherapy. However, the existing TAMs repolarization strategies are restricted by hostile microenvironmental stress and metabolic compensation, leading to limited anti-tumor phenotype sustainability. Herein, a “Spark-Relay” nanoinitiator (SRN) with flexible S/R reactant ratio was meticulously designed for rewiring TAMs as tumoricidal bioreactor and precisely overcome metabolic compensation. Briefly, SRN reshaped TAMs in situ relying on tissue tropism of macrophage membrane, firstly upregulating their reactive oxygen species (ROS) production via burst release of Spark element and initially shifting the TAMs into the anti-tumoral phenotype, subsequently elevating NO production by releasing Relay element, which is converted to NO via reaction with ROS and iNOS, leading to the generation of additional ROS and creating a positive feedback loop, thereby strengthening the metabolic rewiring of TAMs from passively defensive oxidative phosphorylation to positively offensive glycolysis, which significantly enhanced the antitumoral activity of TAMs and shrunk tumor immunosuppressive microenvironment, emerging as 5.5-fold increase of tumor-suppressive/supportive ratio (TSSR) of TAMs, 4.0-fold elevation of CD8⁺ T cell infiltration, contributing to a satisfactory tumoricidal efficacy and providing a cascade amplification mode for TAMs-based cancer therapeutics.

Nanomedicine  /  Controllable ratio  /  Sequential release  /  Tumor-associated macrophages  /  Metabolic reprogramming  /  Solid tumor  /  Reactive oxygen species  /  Nitric oxide