The crosstalk between ferroptosis and anti-tumor immunity in the tumor microenvironment: molecular mechanisms and therapeutic controversy

Abstract

The advent of immunotherapy has significantly reshaped the landscape of cancer treatment, greatly enhancing therapeutic outcomes for multiple types of cancer. However, only a small subset of individuals respond to it, underscoring the urgent need for new methods to improve its response rate. Ferroptosis, a recently discovered form of programmed cell death, has emerged as a promising approach for anti-tumor therapy, with targeting ferroptosis to kill tumors seen as a potentially effective strategy. Numerous studies suggest that inducing ferroptosis can synergistically enhance the effects of immunotherapy, paving the way for a promising combined treatment method in the future. Nevertheless, recent research has raised concerns about the potential negative impacts on anti-tumor immunity as a consequence of inducing ferroptosis, leading to conflicting views within the scientific community about the interplay between ferroptosis and anti-tumor immunity, thereby underscoring the necessity of a comprehensive review of the existing literature on this relationship. Previous reviews on ferroptosis have touched on related content, many focusing primarily on the promoting role of ferroptosis on anti-tumor immunity while overlooking recent evidence on the inhibitory effects of ferroptosis on immunity. Others have concentrated solely on discussing related content either from the perspective of cancer cells and ferroptosis or from immune cells and ferroptosis. Given that both cancer cells and immune cells exist in the tumor microenvironment, a one-sided discussion cannot comprehensively summarize this topic. Therefore, from the perspectives of both tumor cells and tumor-infiltrating immune cells, we systematically summarize the current conflicting views on the interplay between ferroptosis and anti-tumor immunity, intending to provide potential explanations and identify the work needed to establish a translational basis for combined ferroptosis-targeted therapy and immunotherapy in treating tumors.

Keywords: anti-tumor immunity; ferroptosis; ferroptosis-targeted therapy; immunogenic cell death; immunotherapy; tumor microenvironment.