A novel nanomedicine integrating ferroptosis and photothermal therapy, well-suitable for PD-L1-mediated immune checkpoint blockade.

Immunotherapy based on immune checkpoint blockade has emerged as a promising treatment strategy; however, the therapeutic efficacy is limited by the immunosuppressive microenvironment. Here, we developed a novel immune-activated nanoparticle (Fc-SS-Fe/Cu) to address the issue of insufficient immune infiltration. Specifically, the structure of Fc-SS-Fe/Cu collapsed in response to the tumor microenvironment, the ferrocene and disulfide bonds and the released Fe/Cu ions can effectively generate ·OH and deplete GSH to increase oxidative stress, thereby inducing ferroptosis. Withal, the positive feedback mechanisms of "laser-triggered mild-temperature photothermal therapy (PTT), PTT accelerated ferroptosis and LPO accumulation, LPO mediated HSPs down-regulated to promote PTT," effectively triggers immunogenic cell death (ICD) in tumor cells, significantly enhancing their immunogenicity. Moreover, the O-generating ability induced by Fc-SS-Fe/Cu could reverse the hypoxic tumor microenvironment, and importantly, the expression of PD-L1 on tumor cell surfaces could be effectively downregulated by inhibiting the HIF-1 pathways, thereby augmenting the effect of anti-PD-L1 (PD-L1) therapy. Therefore, this study provides valuable strategies into enhancing PD-L1-mediated ICB therapy.