Photo-enhanced Synergistic Induction of Ferroptosis for Anti-Cancer Immunotherapy

Ferroptosis as programmed cell death received considerable attention in Cancer research. Recently, studies have associated Ferroptosis with photodynamic therapy (PDT) because PDT promotes glutathione (GSH) deletion, Glutathione Peroxidase 4 (GPX4) degradation, and lipid peroxide accumulation. However, PDT-induced Ferroptosis might be potentially prevented by Ferroptosis suppressor protein 1 (FSP1), a newly found Ferroptosis inhibitor. To address this limitation, herein, a novel strategy was developed to trigger Ferroptosis by PDT and FSP1 inhibition. For enhancement of this strategy, a photoresponsive nanocomplex, self-assembled by BODIPY-modified PAMAM (BMP), was utilized to stably encapsulate the inhibitor of FSP1 (iFSP1) and chlorin e6 (Ce6). The nanosystem promoted intracellular delivery, penetration, and accumulation of Ferroptosis inducers in tumors with LIGHT irradiation. The nanosystem presented high-performance triggering of Ferroptosis and immunogenic cell death (ICD) in vitro and in vivo. Importantly, the nanoparticles increased tumor infiltration of CD8⁺ T cells and further enhanced the efficacy of anti-PD-L1 immunotherapy. The study suggests the great potential of photo-enhanced synergistic induction of Ferroptosis by the photoresponsive nanocomplexes in Cancer Immunotherapy. This article is protected by copyright. All rights reserved.

BODIPY; PAMAM; charge reversal; ferroptosis; immunotherapy; photodynamic therapy.