Ferroptosis-Strengthened Metabolic and Inflammatory Regulation of Tumor-Associated Macrophages Provokes Potent Tumoricidal Activities

Nano Lett. 2021 Aug 11;21(15):6471-6479. doi: 10.1021/acs.nanolett.1c01401. Epub 2021 Jul 22.

Abstract

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.

Keywords: Macrophage polarization; Metabolic regulation; Metal organic framework; Nanoimmunomodulation; Tumor inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ferroptosis*
  • Humans
  • Macrophages
  • Nanoparticles*
  • Tumor Microenvironment
  • Tumor-Associated Macrophages