Ferroptotic tumor cells reprogram tumor-associated macrophage antigen presentation to enhance the efficacy of immune checkpoint blockade.

Abstract

Although evidence links ferroptosis to tumor immunity, the rationale and translational potential of ferroptosis-based therapy remain unresolved. Here, we show that inducing tumor-cell ferroptosis enhances anti-tumor immunity by potentiating major histocompatibility complex II (MHC-II)-dependent antigen presentation in tumor-infiltrating macrophages. Multi-omics analyses reveal that all-trans retinoic acid (ATRA) released from ferroptotic tumor cells directly targets CD38 through the transcriptional factor retinoic acid receptor alpha (RARα) and activates transcription factor EB (TFEB) to control MHC-II expression in macrophage by inducing autophagy. Clinically, a ferroptosis signature correlates with improved immunotherapy response. We also developed a drug-free nano-redox lever that selectively targets and disrupts glutathione metabolism in hypoxic tumor regions by accepting electrons, thereby potentiating ferroptosis-mediated immune stimulation. This creates a positive feedback loop wherein activated macrophages further promote immune-driven tumor ferroptosis, synergizing with anti-PD-1 (programmed cell death protein 1) therapy across preclinical models. Together, our study identifies an uncovered role for ferroptosis in tumor immunity and provides a clinically translatable approach to enhance immunotherapy efficacy.