Cancers only develop if they escape immunosurveillance, and the success of cancer therapies relies in most cases on their ability to restore effector T-cell functions, particularly their capacity to produce IFN- g. Revolutionizing the treatment of many cancers, immunotherapies targeting immune checkpoints such as PD-1 increase patient survival. Unfortunately, only a minority of patients respond successfully to anti-PD-1 immunotherapy, making it crucial to identify alternative treatments that could be combined with current immunotherapies to improve their effectiveness.
Using several approaches, we were able to demonstrate that iron significantly increases T cell responses in vitro and in vivo. In vitro, we observed that iron supplementation led to an increase in the activation and proliferation of naive CD4+ and CD8+ T cells. In vivo, this "adjuvant" effect translates into a strong growth slowdown of transplanted tumors in mice. In this context, iron promotes the differentiation/expansion of type I effector T cells, characterized by the expression of the transcription factor T-bet as well as their high capacity of IFN-γ production. Furthermore, we observed that the growth of tumor cell lines deficient in either ACSL4 enzyme production or IFN-γ receptor expression, which are key factors in ferroptosis induction, was less affected by iron supplementation after transplantation in mice than the control line. Thus, our results demonstrate that the iron-induced anti-tumor response of T cells would cause cancer cell death by induction of ferroptosis.
In parallel, we analyzed the effect of iron in conjunction with anti-PD-1 immunotherapy. We tested a tumor line known to be "responsive" to anti-PD-1 immunotherapy and observed that iron supplementation significantly increases the efficacy of the immunotherapy. We also obtained encouraging results using a tumor line known to be "resistant" to anti-PD-1 immunotherapy where in this case iron supplementation allows the transplanted mice to respond to anti-PD-1 treatment and thus control the growth of these tumors.
Finally, in a cohort of 35 cancer patients, we were able to demonstrate that those with normal iron levels at the start of anti-PD-1 treatment had a stronger pro-Th1 cytokine response 3 weeks after the first injection than iron-deficient patients.
Together, these findings suggest that the efficacy of immunotherapy could be improved by enhancing and modulating the T-cell response with one of the most classical chemical elements, iron.

Keywords: iron, cancer, immunotherapy, Th1, IFN-g, ferroptosis