Dendritic cells (DCs) are antigen-presenting cells of the immune system, which play a key role in antitumor immunity by activating cytotoxic T cells. Here, we report that elevated ferroptosis, a lipid peroxidation-mediated cell death, impairs the maturation of DCs and their function in tumor suppression. Ferroptosis is selectively induced in DCs by the GXP4 inhibitor RSL3, but not the SLC7A11 inhibitor erastin. Ferroptotic DCs lose their ability to secrete pro-inflammatory cytokines (TNF and IL6) and express MHC class I in response to the maturation signal of lipopolysaccharide. Moreover, ferroptotic DCs fail to induce CD8⁺ T cells to produce IFNG/IFNγ. Mechanistically, PPARG/PPARγ, a nuclear receptor involved in the regulation of lipid metabolism, is responsible for RSL3-induced ferroptosis in DCs. Consequently, the genetic depletion of PPARG restores the maturation and function of DCs. Using immunogenic cell death-based DC vaccine models, we further demonstrate that PPARG-mediated ferroptosis of DCs limits antitumor immunity in mice. Together, these findings demonstrate a novel role of ferroptotic DCs in driving an immunosuppressive tumor microenvironment.

树突状细胞 (DC) 是免疫系统的抗原呈递细胞，通过激活细胞毒性 T 细胞在抗肿瘤免疫中发挥关键作用。在这里，我们报告了升高的铁死亡，脂质过氧化介导的细胞死亡，损害 DC 的成熟及其在肿瘤抑制中的功能。铁死亡是由 GXP4 抑制剂 RSL3 在 DC 中选择性诱导的，但不是 SLC7A11 抑制剂erastin。铁死亡 DCs 失去分泌促炎细胞因子（TNF 和 IL6）的能力，并响应脂多糖的成熟信号表达 MHC I 类。此外，铁死亡 DCs 不能诱导 CD8 ⁺T 细胞产生 IFNG/IFNγ。从机制上讲，PPARG/PPARγ 是一种参与脂质代谢调节的核受体，负责 RSL3 诱导的 DC 铁死亡。因此，PPARG 的遗传耗竭恢复了 DC 的成熟和功能。使用基于免疫原性细胞死亡的 DC 疫苗模型，我们进一步证明 PPARG 介导的 DC 铁死亡限制了小鼠的抗肿瘤免疫。总之，这些发现证明了铁死亡 DC 在驱动免疫抑制性肿瘤微环境中的新作用。