Search

Due to the pro-survival effect of mild autophagy, the therapeutic effect of chemo-immunotherapy is unsatisfactory. In addition, the adverse tumour microenvironment (TME), including the lack of antigen presentation, the deficiency of oxygen supply and immunosuppressive cells, results in immune escape and metastasis. Herein, a novel nanoplatform (CS–3BP/PA@DOX) based on the autophagy cascade is proposed for the first time to deliver the chemotherapeutic doxorubicin (DOX) and respiration inhibitor 3-bromopyruvic acid (3BP) to overcome the above obstacles. CS-3BP/PA@DOX exerts a synergistic therapeutic effect to initiate pro-death autophagy and facilitate the antigen presentation process by combining DOX chemotherapy and starvation therapy with 3BP. Additionally, CS-3BP/PA@DOX remodelled the immunosuppressive TME by alleviating hypoxia, damaging dense ECM, and downregulating PD-L1 to enhance antitumour immunity. 3BP was found to promote GSH depletion by inhibiting respiration for the first time, which reduces the chemical resistance of cancer and increases the sensitivity of cells to ROS, providing a new therapeutic direction of 3BP for antitumour treatment. Collectively, this study offers an opportunity to magnify pro-death autophagy, augment antitumour efficacy, facilitate anti-metastatic effects, and boost immune responses. [Display omitted] • CS-3BP/PA@DOX exerted a synergistic therapeutic effect to treat breast cancer. • This nanoplatform augmented anti-tumor efficacy and boosted immune responses. • CS-3BP/PA@DOX remodelled immunosuppressive tumor microenvironment. [ABSTRACT FROM AUTHOR]

• Tumor-specific deep penetration is realized by p-LDM. • Ferroptosis sensitization can be achieved by CA IX inhibition. • Self-amplified ferroptosis is realized by two structural components of p-LDM. • "p-LDM + anti-CD47" achieves enhanced therapeutic efficiency. As an approved chemotherapeutic drug for breast cancer (BC) therapy, the continuous application of doxorubicin (DOX) is unfortunately limited by its poor selectivity and the apoptosis resistance of tumor cells. To cope with the obstacles, this work developed a tumor-specific nanoplatform (named p-LDM) for DOX delivery and combinational ferroptosis-apoptosis activation. p-LDM was fabricated by coating ferric metal–organic framework (MOF) with liposomes and the outer liposomal membrane was further interspersed with targeting peptide-conjugated enzyme-activatiable cell-penetrating peptides (CPPs) to guarantee the tumor-specific penetration. As two components of the MOF core, Fe3+ (metal ion junction) triggered the ferroptosis of 4T1 cells via its self-cyclic valence alteration and terephthalic acid (H 2 BDC, organic ligand) reinforced the Fe3+-triggered ferroptosis by inhibiting carbonic anhydrase IX (CA IX); this self-amplifying strategy delicately boosted robust tumor ferroptosis. By combining DOX and ferroptosis activation, p-LDM performed forceful direct killing effect, immungentic cell death (ICD) stimulation, T cell activation and dendritic cell (DC) maturation promotion, suggesting its potential for synergetic apoptosis/ferroptosis activation and tumor immune microenvironment (TIM) remodeling. Further, p-LDM was combined with CD47-SIRPα blockade therapy, generating reinforced ferroptosis, which was largely attributed to the maximal up-regulation of IFN-γ levels and consequent system Xc- inhibition. Besides, the released "find me" signal from ferroptosis, "eat me" signal from ICD and the inhibited CD47-released "don't eat me" signal jointly remodeled the suppressive TIM, receiving superior synergistic inhibitions on tumor growth, metastasis and recurrence. [ABSTRACT FROM AUTHOR]