Leveraging the Tumor Immunogenic Effects of Ferroptosis to Rationally Design Effective Immune Based Therapies

Effective combination immunotherapy regimens increase the success rate of treating cancer patients than either monotherapy alone. Ferroptosis is a novel form of cell death that has gained popularity in the last decade as a potential tool to be used against cancer progression but has not had much success clinically. Currently, several groups are studying the relevance of ferroptosis in the context of immunotherapy in an attempt to expand its clinical translatability as well as to overcome the lack of response to immunotherapy alone. The field though is divided regarding the nature of the effects of ferroptosis inducers on the immune system. While some reports suggest that ferroptosis inducers are immunosuppressive, others demonstrate the immune promoting effects elicited by ferroptosis, making it hard to effectively design a combination therapy with clinical potential. A possible explanation is the use of different tumor models or different types of ferroptosis inducers across these studies. In order to rigorously interrogate the use ferroptosis in an immunotherapy regimen, we have evaluated the impact of different classes of ferroptosis inducers with various different immune modulators in several pre-clinical cancer models both in vivo and in vitro. Interestingly, we observed that within the same preclinical model of metastatic melanoma, the choice of the immune modulator used can significantly alter the directionality of the effects of ferroptosis on tumor progression. We confirm that treatment with ferroptosis inducers increases the ability of tumor cells to activate T cells in vitro irrespective of the type of inducer. On the other hand, the quality of immune response in vivo, varies with the class of ferroptosis inducer. We subsequently, designed a regimen with a CD40 agonist that boosts the tumor immunogenic impact of ferroptosis and enhances the activation of the adaptive immune system. This regimen reduces the progression of the treated tumor, elicits an abscopal effect and improves the survival of mice as well. While FDA approved immune checkpoint blockade such as anti-PD1 therapy elicits variable responses based on the type of ferroptosis inducer used, our regimen is effective with either class of ferroptosis inducer in both melanoma and colon cancer pre-clinical models. We are also able to abrogate the effect of each class of ferroptosis inducers by using a ferroptosis inhibitor. Thus, our study evaluates for the first time the contribution of ferroptosis to immune based therapies without the confounding effects due to the chemistry of the small molecule used. In conclusion, our data resolves the conflicting reports about the immune effects of ferroptosis and paves the way for evaluating the clinical efficacy of ferroptosis in combination with appropriate immune modulators. Citation Format: Divya Venkatesh, Daniel Thach, Qian Wang, Rachana R Maniyar, Iken Takiyeddine, Mariam M George, Isabell Schulze, Hengrui Liu, Brent R Stockwell, Jedd D Wolchok, Taha Merghoub. Leveraging the tumor immunogenic effects of ferroptosis to rationally design effective immune based therapies [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B011.