Inducing ferroptosis to improve cancer therapy: a promising tool for enhancing immunotherapy

The discovery of ferroptosis as a novel mechanism of cell death has opened the door to a new scenario in which it could be used to support current cancer therapy, particularly in cases of relapse. Several compounds have been developed aimed to inhibit or induce ferroptosis in cancer cells by acting on different signaling pathways caable of activating or repressing, respectively, this cell death mechanism.

This review shows how treatmenting cancer cells with ferroptosis inducers results in improved efficacy of immunotherapy. Indeed, the advantage of affecting ferroptosis lies in the capacity of compounds to improve immune system compartments. The involvement of ferroptosis in cancer treatment is now emerging, demonstrating the high translational potential of this approach capable of carrying out an immune response against tumors, dendritic cells (DC), regulatory T cells (Treg), Natural Killer cells (NK) and tumor-associated macrophages (TAM) exert an interesting role. Some immune check-point inhibitors (ICIs) have been approved as cancer immunotherapy, because they target cytotoxic T lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD-1) and its ligand PD-L1. For this reason, promising results have been achieved by combining ferroptosis inducers with ICIs. At the same time, combining Chimeric Antigen Receptor (CAR) T-cell therapy with ferroptosis inducers shows promising anti-tumor activity, particularly in solid tumors. This approach demonstrates how the modulation of ferroptosis may improve the efficacy of CAR T-cells treatment by promoting tumor cell death and enhancing immunogenicity.

In conclusion the development of clinical trials aimed at testing the efficacy of ferroptosis induction in combination with current cancer therapy will be the definitive proof of the valid opportunity provided by this therapeutic approach.