Reprogramming tumor-associated macrophages (TAMs) from tumor-supportive M2 phenotype to anti-tumor M1 phenotype holds great promise in tumor immunotherapy. However, there are few reports on the remodeling of TAMs by inorganic nanoparticles due to their unclear intrinsic polarization mechanism. In this article, a novel signaling pathway of repolarizing TAMs into M1-like macrophages is reported to boost anti-tumor immunity using ultra-small Cu2���xSe nanoparticles (CS NPs). The mechanism is totally different from the conventional ROS-mediated polarization mechanism. It is revealed that CS NPs can effectively generate ROS in the macrophages to trigger auto-ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6), which activates the interferon regulatory factor 5 (IRF5) to facilitate the expression of its downstream gene interleukin-23 (IL-23), and eventually remodels the TAMs into M1-like macrophages. It is shown that CS NPs can significantly inhibit the growth of melanoma tumor (B16F10) by repolarizing TAMs into M1-like macrophages, and enhance the adaptive anti-tumor immunity by inducing the infiltration of CD8+ T cells. Moreover, it is found that CS NPs can also effectively inhibit the recurrence of distal tumor. The study shows the novel macrophage polarization mechanism for TAMs-targeted cancer immunotherapy, and demonstrates the great potential of ultra-small Cu2���xSe nanoparticles in cancer immunotherapy.