Tumor Microenvironment Mediated Spermidine-Metal-Immunopeptide Nanocomplex for Boosting Ferroptotic Immunotherapy of Lymphoma

Abstract

Immunotherapy as an alternative treatment strategy for B-cell lymphoma is undesirable because of tumor heterogeneity and immune surveillance. Spermidine (SPM), as a regulator of the tumor microenvironment (TME), can facilitate the release of damage-associated molecular patterns (DAMPs) from cancer cells, promote immune recognition, and thus alleviate immune surveillance in the TME. Hence, in this work, self-assembled spermidine-based metal-immunopeptide nanocomplexes (APP-Fe NCs; APP is anti-programmed death ligand-1 peptide) with pH-responsive release kinetics were prepared via the flash nanocomplexation (FNC) technique based on the noncovalent interaction between APP-SPM-dextran (DEX) and sodium tripolyphosphate (TPP) and coordination between Fe³⁺ and TPP. An <i>in vitro</i> study suggested that APP-Fe NCs effectively induce strong oxidative stress and mitochondrial dysfunction and subsequently lead to ferroptosis in cells by interfering with homeostasis in lymphoma cells. Further investigation on lymphoma mice models demonstrated that APP-Fe NCs effectively inhibited the growth and liver metastasis of lymphomas. Mechanistically, by triggering ferroptosis in tumor tissues, these spermidine-containing APP-Fe NCs efficiently facilitated the release of DAMPs and ultimately reshaped TME to enhance immunotherapy efficacy in lymphoma. Combined with its good histocompatibility and facile preparation technique, this pH-responsive APP-Fe NCs with regulation on TME may hold potential for cascade amplification on the combinative immunotherapy of lymphoma in the clinic.