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 Fe 3+ and TPP. An in vitro 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.

Cascade Amplification of Pyroptosis and Apoptosis for Cancer Therapy through a Black Phosphorous-Doped Thermosensitive Hydrogel

“…Theoretically, local hyperthermia may induce cell death and promote the release of damage-associated molecular patterns (DAMPs), an inflammatory response in defending infection [ 38 ]. Hence, it is reasonable to deduce there exists an interplay between hyperthermia and a proinflammatory cell death pathway, i.e., pyroptosis.…”

The crosstalk between ferroptosis and anti‐tumor immunity in the tumor microenvironment: molecular mechanisms and therapeutic controversy

“…Furthermore, recent studies, particularly those focused on nanoparticle‐based approaches, have provided ample evidence for the immunomodulatory effects of inducing ferroptosis in cancer cells. For example, many studies have demonstrated that ferroptotic cancer cells promote immune cell infiltration or activation, thereby improving the immunosuppressive TME [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 62 , 79 , 84 , 85 , 118 , 119 , 120 , 121 , 122 ]. Several studies have also shown that inducing ferroptosis in cancer cells significantly enhances the efficacy of immunotherapy [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ].…”

The improving strategies and applications of nanotechnology-based drugs in hepatocellular carcinoma treatment

“…More preclinical data are needed to promote the progress of clinical applications. In addition, some nanoparticles also respond to external stimuli such as ultrasonic stimulation, heat, pH, and light, and these types of nanoparticles could release drugs in a controlled manner, thereby improving the precision and targeting of drug delivery ( Liu et al, 2023 ; Nie et al, 2023 ), such as pH-sensitive targeting of gastrointestinal and vaginal delivery systems ( Abdella et al, 2023 ), extracellular matrix sensitive GNPs-Dox-Lac ( Liu et al, 2018 ) and magnetic Fe 3 O 4 nanoparticles ( Chen and Hou, 2022 ) At present, physical and chemical targeted nanodrug delivery systems have shown great potential in animal models, but the physical and chemical properties in vivo are dynamic, and how to accurately set the stimulus perception of nanodrug delivery vectors remains to be further studied.…”