Albumin nanoassembly bi-directionally manipulated ferroptosis in tumor and CD8+ T cells for triple-negative breast cancer therapy
Ting Yang, Zihan Liu, Zixuan Fu, Xiaojie Zhang, Yongjin Cao, Qiangwei Liang, Jiale Miao, Hao Yang, Tong Zhang, Jing Hei, Weiqing Ni, Yanhua Liu
Abstract
Ferroptosis can serve as a potent strategy for regulating cell death via lipid peroxidation and the imbalance of the antioxidant system resulting from iron accumulation in triple-negative breast cancer (TNBC) therapy. However, the ferroptosis accompanied with down-regulation of glutathione peroxidase 4 (GPX4) lead to CD36-mediated tumor-infiltrating CD8 + T cells uptaking fatty acids, resulting in the negative action on immunotherapeutic efficacy. Herein, the albumin nanoparticles, abbreviated as LHS NPs, were designed by co-assembly of hemin, linoleic acid-cystamine, and a CD36 inhibitor sulfosuccinimide oleate, to bi-directionally manipulated ferroptosis in tumor and CD8 + T cells for TNBC therapy. LHS NPs exerted more efficient reactive oxygen species generation, glutathione depletion and malondialdehyde production by the combinatory strategy of classical and non-classical ferroptosis modes, which amplified the positive action on ferroptosis in tumor cells. Meanwhile, LHS manipulated the negative action of ferroptosis by inhibiting the CD36 mediated-lipid peroxidation in CD8 + T cells, thereby activating the immunotherapeutic efficacy with the improvements on induction of immunogenic cell death, proliferation of CD4 + CD8 + T cells and natural killer cells, alleviation immunosuppressive regulatory T cells and myeloid-derived suppressor cells, and repolarization of the M2- to M1-phenotype tumor-associated macrophages. Thus, LHS NPs demonstrated an improved antitumor efficacy in suppressing the tumor growth and lung metastasis of 4T1-tumor mice. Our work gives novel insights for the bi-directionally manipulating ferroptosis in tumor and CD8 + T cells on TNBC chemoimmunotherapy. The three-in-one nanoassembly of LHS NPs were developed by co-assembling hemin, LA-Cys and SSO with the assistance of human serum albumin. LHS NPs amplified the positive action of ferroptosis in tumor cells by enhancement of ROS production, GSH depletion and lipid peroxides accumulation. The negative action of ferroptosis was potently manipulated via inhibiting the CD36 mediated-lipid peroxidation in CD8 + T cells, thereby activating the immunotherapeutic efficacy. Thus, LHS NPs demonstrated a potent chemoimmunotherapy efficacy in suppressing the tumor growth and lung metastasis in 4T1 triple-negative breast cancer. Figure created using Figdraw.