Fe/Al-LDH Nanomedicine for Antitumor Ferroptosis-Immunotherapy by Immunosuppression Reversal

Ferroptosis is recognized as a novel type of programmed cell death with efficient immunogenicity to activate T cell-mediated adaptive immune responses. However, conventional ferroptosis-inducers mostly show poor efficacies due to their less effectiveness in immune regulation. In addition, suppression of T cells by M2-type macrophages within the tumor microenvironment further weaken the immunotherapeutic effect of ferroptosis. To overcome these challenges, herein, an extremely simple Fe/Al-layered double hydroxide (Fe/Al-LDH) nanomedicine of enhanced iron concentration is reported, which is capable of selective degradation in acidic microenvironments to induce tumor cell ferroptosis and in the meantime reversing the immunosuppressive microenvironment by utilizing tumor cell ferroptosis and macrophage M1 polarization to synergistically enhance T cell immune response. This combined strategy has achieved excellent therapeutic efficacy in an orthotopic bilateral breast cancer model, demonstrating the great application potential of Fe/Al-layered double hydroxide nanoplatform for iron ions-regulated cancer immunotherapy. An extremely simple nanomaterial is synthesized, Fe/Al-layered double hydroxide (Fe/Al-LDH), featuring the enhanced iron amount and pH-sensitive biodegradation, to induce tumor cells ferroptosis and macrophage M1 polarization for enhanced antitumor immunotherapy. The combined therapeutic strategy provides a simple, effective, and biosafe nanoplatform for the systemic delivery of iron ions to reverse tumor immunosuppressive microenvironment and enhance antitumor ferroptosis-immunotherapy. image