Ferroptotic tumor cells revamp tumor-associated macrophage antigen presentation to unleash immune checkpoint blockade efficacy

Herein, we show that inducing tumor cell ferroptosis boosts anti-tumor immunity by potentiating major histocompatibility complex II (MHC-II)- dependent antigen presentation in tumor-infiltrating macrophages. Supporting our findings with multi-omics data, we reported that ferroptotic tumor-derived all-trans retinoic acid (ATRA) is a novel regulator of MHC-II in macrophages.

ATRA directly targets CD38 through transcriptional factor RARα and activates master regulator TFEB to control MHC-II expression by inducing autophagy. Clinically, a ferroptosis signature is associated with better immunotherapy response. We also innovatively develop a drug-free nano-redox lever (DFNRL) to circumvent the non-specific limitations of conventional drugs, which specifically targets and disrupts glutathione metabolism in tumor cells by accepting electrons, thereby boosting ferroptosis-mediated immune stimulation.