"Ferroptosis is a therapeutically exploitable for cancer treatment but its effects on the immune system as paradoxical. Ferroptosis can induce immunogenic cell death while also being able to impair immune fitness to blunt immunotherapy in other contexts. To harness its pro-immune potential, we used multi-omics profiling (scRNA + CITE-seq, TCR-seq, flow cytometry) across several contexts. We uncovered that ferroptosis enhances tumor antigenicity while simultaneously eliciting immunosuppression even within the same context, overall impairing immune checkpoint blockade (ICB)efficacy. On the other hand, stimulation of antigen presenting cells (APCs) by CD40 agonism rewires this response to convert ferroptosis from a net immunosuppressive to a net immunostimulatory cue. The ferroptosis-CD40 regimen induces inflammatory dendritic cells, expands clonally active T/B cells, reprograms neutrophils, and delays tumor growth. The triple combination with ICB now (ferroptosis inducer + CD40 + ICB) achieves potent and durable tumor control. We have been able to generalize this ""ferroptosis switch"" across ferroptosis inducers and sensitive/resistant tumors. Through this study, we can demonstrate that ferroptosis can exert concurrent competing effects that can be dictated by APC wiring at induction. Finally, our pre-clinical results demonstrate that CD40 agonism is able to unlock ferroptosis's pro-immune potential to establish a clinically translatable immunotherapy combination.

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