Enhanced\nImmunogenic Cell Death by Apoptosis/Ferroptosis\nHybrid Pathway Potentiates PD-L1 Blockade Cancer Immunotherapy

Abstract

Even though chemotherapy regimens for treating cancer\nby inducing\napoptosis are extensively utilized, their therapeutic effect is hindered\nby multiple limitations. Thus, a combination of other types of anticancer\nmodalities is urgently needed. Herein, a tannic acid (TA)-Fe³⁺-coated doxorubicin (DOX)-encapsulated 1,2-distearoyl-<i>sn</i>-glycero-3-phosphoethanolamine-<i>N</i>-[methoxy(poly(ethylene\nglycol))-2000] (ammonium salt) (DSPE-PEG) micelle (TFDD) for apoptosis/ferroptosis-mediated\nimmunogenic cell death (ICD) is reported. By coating TA-Fe³⁺ on the surface of DOX-loaded micelles, an apoptotic agent and a\nferroptotic agent are simultaneously delivered into the cancer cells\nand induce cell death. Furthermore, the intracellular oxidative environment\ngenerated by the apoptosis/ferroptosis hybrid pathway stimulates the\nendoplasmic reticulum (ER) and leads to ICD induction. The in vivo\nresults show that the combination treatment of TFDD and anti-programmed\ndeath-ligand 1 antibodies (anti-PD-L1) considerably inhibits tumor\ngrowth and improves antitumor immunity by activating CD4⁺ and CD8⁺ T cells and decreasing the ratio of regulatory\nT cells (Treg) to CD4⁺ T cells. This study suggests that\nthe apoptosis/ferroptosis-mediated ICD inducer may offer a potent\nstrategy for enhanced cancer immunotherapy.