To improve the treatment efficiency and targeted enrichment ability of tumors, in this study, a nanoplatform (FeCuSe@MONs-ART@HA) based iron copper selenide@mesoporous organosilica nanoparticles (FeCuSe@MONs) has been designed for synergistic chemotherapy (CT), photothermal therapy (PTT), and chemodynamic therapy (CDT). The photothermal performance and peroxidase-like activity of FeCuSe@MONs generated PTT-CDT synergistic therapy. The densely coated hyaluronic acid (HA) layers on the surface of FeCuSe@MONs not only improved the cancer-targeting efficiency but also prevented the nonspecific release of artesunate (ART). The high concentration of glutathione (GSH) and acid tumor microenvironment triggered the release of ART for chemotherapy, which simultaneously augmented the CDT efficiency of FeCuSe@MONs. Additionally, the glutathione peroxidase 4 (GPX4) levels significantly declined. MTT assay results indicated that FeCuSe@MONs-ART@HA demonstrates superior cytotoxic effects compared to FeCuSe@MONs@HA and ART alone. Furthermore, cells viability decreased to 18.75 % upon the application of an 808 nm laser. In vivo investigations further revealed that the FeCuSe@MONs-ART@HA + laser treatment group exhibited the highest rate of tumor growth inhibition, TGI% value reaching nearly 87.3 %, which was much higher than the 31.2 %, 45.6 % and 76.5 % in the groups of ART, FeCuSe@MONs@HA and FeCuSe@MONs@HA + laser. Owing to the synergistic effect, this nanoplatform significantly improved antitumor efficacy with minimal toxicity both in vitro and in vivo. These findings highlight such a CT-PTT-CDT synergistic drug delivery system showed great potential for treating tumors.