Macrophage-inherited exosome excise tumor immunosuppression to expedite immune-activated ferroptosis

J Immunother Cancer. 2023 May;11(5):e006516. doi: 10.1136/jitc-2022-006516.

Abstract

Background: Immunosuppressive tumor microenvironment (ITM) remains an obstacle that jeopardizes clinical immunotherapy.

Methods: To address this concern, we have engineered an exosome inherited from M1-pheototype macrophages, which thereby retain functions and ingredients of the parent M1-phenotype macrophages. The delivered RSL3 that serves as a common ferroptosis inducer can reduce the levels of ferroptosis hallmarkers (eg, glutathione and glutathione peroxidase 4), break the redox homeostasis to magnify oxidative stress accumulation, promote the expression of ferroptosis-related proteins, and induce robust ferroptosis of tumor cells, accompanied with which systematic immune response activation can bbe realized. M1 macrophage-derived exosomes can inherit more functions and genetic substances than nanovesicles since nanovesicles inevitably suffer from substance and function loss caused by extrusion-arised structural damage.

Results: Inspired by it, spontaneous homing to tumor and M2-like macrophage polarization into M1-like ones are attained, which not only significantly magnify oxidative stress but also mitigate ITM including M2-like macrophage polarization and regulatory T cell decrease, and regulate death pathways.

Conclusions: All these actions accomplish a synergistic antitumor enhancement against tumor progression, thus paving a general route to mitigate ITM, activate immune responses, and magnify ferroptosis.

Keywords: Tumor Microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bioengineering / methods
  • Carbolines* / pharmacology
  • Cell Line, Tumor
  • Exosomes* / chemistry
  • Exosomes* / metabolism
  • Ferroptosis* / drug effects
  • Immunotherapy
  • Macrophages* / metabolism
  • Mice
  • Neoplasms* / immunology
  • Neoplasms* / therapy
  • Tumor Microenvironment

Substances

  • RSL3 compound
  • Carbolines