A novel nanomedicine integrating ferroptosis and photothermal therapy, well-suitable for PD-L1-mediated immune checkpoint blockade
Yujun Bao, Guanghao Li, Siqi Li, Haishui Zhou, Ziqing Yang, Zhiqiang Wang, Rui Yan, Changhong Guo, Yingxue Jin
Abstract
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 2 -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 α pathways, thereby augmenting the effect of anti-PD-L1 ( α PD-L1) therapy. Therefore, this study provides valuable strategies into enhancing PD-L1-mediated ICB therapy. • Fc-SS-Fe/Cu was prepared by skillfully conjugating ferrocene and disulfide bonds. • Fc-SS-Fe/Cu showed potential as a drug carrier with the outstanding biodegradability. • Fc-SS-Fe/Cu activated immunotherapy by inducing ICD through ferroptosis and PTT. • Fc-SS-Fe/Cu could downregulate PD-L1 expression by inhibiting the HIF-1 α pathway. • Fc-SS-Fe/Cu could effectively enhance the therapeutic effects of anti-PD-L1 antibody.