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

ABSTRACT: Activation of antigen presentation has been shown to contribute to improved immunotherapy outcomes. 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. This synergizes with anti–PD-1 immunotherapy across preclinical models. Our study answers an unidentified role for ferroptosis in modulating anti-tumor immunity and provides a clinically translatable approach to enhance immunotherapy efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE318119 | GEO | 2026/03/15

REPOSITORIES: GEO

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