Conditional knock-out of Transferrin receptor 1 in Alb-cre H11-myc mice

Disrupted iron metabolism is commonly observed in various types of cancer. However, the role of iron signaling in controlling the tumor microenvironment and its clinical relevance remain unclear. We found that intra-tumoral iron signals stabilized PD-L1 protein, dampening CD8+ T cell responses and promoting tumor evasion. Blocking iron uptake decreased PD-L1 expression and enhanced CD8+ T cell infiltration, leading to attenuated tumor growth. Mechanistically, iron preserved PD-L1 protein integrity by inhibiting its ubiquitination. Iron-induced lipid peroxidation in tumors promoted the generation of 4-Hydroxynonenal (4-HNE), which subsequently adducted to the PD-L1 cytoplasmic domain for its carbonylation. 4-HNE-mediated carbonylation outcompeted PD-L1 ubiquitination, resulting in PD-L1 protein stabilization. Finally, we introduced a designed peptide in tumor cells to diminish PD-L1 carbonylation by competing for 4-HNE availability. This led to decreased PD-L1 expression and enhanced CD8+ T cell immunity, hindering tumor growth. Importantly, such peptide therapy showed effective outcomes in anti-PD-L1 non-responding tumors. Thus, our findings reveal alternative strategies for overcoming PD-L1-mediated immune evasion in cancer.