Nanoplatforms synchronously activating tumor cell ferroptosis and remodeling the tumor microenvironment for reinforced cancer therapeutics

Abstract

Ferroptosis is a form of iron-dependent cell death pattern distinct from apoptosis, providing new targets for cancer therapeutics. By regulating cellular iron metabolism, destroying redox imbalance defenses and/or promoting lipid peroxidation, ferroptotic therapy induces ferroptosis of tumor cells, thereby circumventing resistance issues associated with the overwhelmingly used apoptosis-based treatments. Importantly, there are myriad interactions between ferroptotic tumor cells and the tumor microenvironment (TME), especially for solid tumors, which would greatly impact therapeutic outcomes. Therefore, it is crucial to simultaneously manipulate tumor cell ferroptosis and TME modulation through rational drug combinations, necessitating the development of relevant nanoplatforms. This review begins by elaborating on the interactions between ferroptotic tumor cells and the TME: on one hand, ferroptosis of tumor cells may activate or suppress immune cells in the TME through diverse mechanisms; on the other hand, the TME (considering its special components and properties) may alter the susceptibility of tumor cells to ferroptotic therapy. Next, we focus on recently reported nanoplatforms capable of simultaneously activating tumor cell ferroptosis and remodeling the TME, providing a systematic analysis of nanoplatform design/construction, drug combination strategies, as well as their advantages and disadvantages. Given the importance of the interactions between tumor cell ferroptosis and the TME, this work aims to offer valuable insights for the exploration of novel targets for reinforced anti-tumor treatment and the design of relevant nanoplatforms.