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.
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