Modulation of tumor-associated macrophages (TAMs) holds promise for cancer treatment, mainly relying on M1 signaling activation and pro-inflammatory promotion. Nevertheless, the antitumor activity is often limited by the anti-inflammatory factors in the tumor microenvironment. Moreover, the metabolic function of TAMs is also critical to tumor progression. However, there are a few strategies that can simultaneously regulate both inflammatory and metabolic functions to achieve safe and potent antitumor activation of TAMs. Herein, we demonstrate that an iron-based metal organic framework nanoparticle and a ferroptosis-inducing agent synergistically induce mitochondrial alternation in TAMs, resulting in a radical metabolic switch from mitochondrial oxidative phosphorylation to glycolysis, which is resistant to anti-inflammatory stimuli challenge. The ferroptosis stress strengthened by the nanoformulation also drives multiple pro-inflammatory signaling pathways, enabling macrophage activation with potent tumoricidal activities. The ferroptosis-strengthened macrophage regulation strategy present in this study paves the way for TAM-centered antitumoral treatment to overcome the limitations of conventional methods.