Immunomodulatory Pd-FePorP nanozyme for inhibition of tumor invasion and metastasis by reinforced ferroptosis and specific epithelial-mesenchymal reversal

Conventional immunotherapies for metastatic cancers remain highly challenging due to insufficient immunity response. Herein, we show that Pd-FePorP significantly triggers ferroptosis mediated-ICD and cooperatively reverses EMT, leading to efficient abrogation of tumor spreading, metastatic invasion and improved immunotherapy outcomes. The maximum catalytic velocity ( V max ) of Pd-FePorP was improved to ∼9.8-fold through in-situ ligand exchange strategy, which eventually induces specific ferroptosis-mediated ICD. Excitingly, Pd-FePorP reverses epithelial-mesenchymal transition (EMT) by upregulating cytokeratin and E-cadherin through inhibition of PI3K/AKT signaling pathway, which could thus interrupt the metastasis cascade to significantly inhibit primary tumor cells migration and invasion. In mouse model, the pretreatment with Pd-FePorP induces EMT reversal in tumor cells, thereby impeding their recolonization in lung tissues and leading to 99 % reduction in lung metastasis nodules. Additionally, when combined with ICD effect induced by ferroptosis, Pd-FePorP synergistically improves the immunosuppressive microenvironment in primary tumor, resulting in effective inhibition of lung metastasis. Our approach may open a new avenue to explore nanozyme as synergistic therapeutic strategy through cooperation between catalysis of smart nanozyme system and EMT reversal for combating cancer metastasis.