Polymeric nano-formulation of spectrum selective RTK inhibitor strengthens anti-cancer effects via immune remodeling by endoplasmic reticulum stress-modulating mitochondrial metabolism

The tumor microenvironment (TME), where immunosuppressive cells such as tumor-associated macrophages (TAMs) proliferate, is the main cause of resistance to antineoplastic treatment for KRAS-driven lung cancer. In this study, we synthesized polymer-based nanoparticles composed of a 16 nm-sized Au cor...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Nano today 2024-02, Vol.54, p.102070, Article 102070
Hauptverfasser: Chang, Li-Chan, Chin, Yu-Cheng, Wu, Ping-Ching, Wei, Yu-Feng, Wu, Hung-Chang, Cheng, Ting-Yu, Liu, Yin-Fen, Huang, Chih-Chia, Su, Wen-Pin
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:The tumor microenvironment (TME), where immunosuppressive cells such as tumor-associated macrophages (TAMs) proliferate, is the main cause of resistance to antineoplastic treatment for KRAS-driven lung cancer. In this study, we synthesized polymer-based nanoparticles composed of a 16 nm-sized Au core and the amphiphile, poly-(styrene-alt-maleic acid) (PSMA), via a hydrothermal procedure for carrying the multi-receptor tyrosine kinase inhibitor, sitravatinib (Sit), in a new nanodrug (Au@PSMA-Sit). Au@PSMA-Sit was water soluble and showed high sitravatinib loading and good stability under numerous solution conditions, and was degraded by intracellular esterase to release sitravatinib. In Lewis lung carcinoma (LLC) orthotopic tumor mice, Au@PSMA-Sit enhanced antitumor efficiency by remodeling the TME. Immune profiling with single-cell RNA sequencing showed that Au@PSMA-Sit treatment increased the CD8 T cell cluster and decreased the M2-type macrophage cluster compared to treatment with pure sitravatinib. Au@PSMA-Sit reduced LLC cell proliferation and upgraded M1 polarization of LLC-cocultured TAMs through inhibition of TAM receptors (Tyro3, AXL, and MerTK) after intracellular release of sitravatinib. Au@PSMA-Sit promoted endocytosis-induced endoplasmic reticulum (ER) stress-mediated spleen tyrosine kinase signaling activation, which regulated immunosuppressive TAMs metabolism via enhancement of mitochondrial fission and glycolysis leading to immunogenic modulation. Furthermore, Au@PSMA-Sit enhanced immunogenic cell death through endocytosis/ER stress-mediated release of CRT and HMGB1 from LLC cells, leading to dendritic cell maturation and cytotoxic T cell activation. Therefore, macrophage and CD8 T cell depletion using blocking antibodies diminished the antitumor efficiency of Au@PSMA-Sit. Our results indicate the potential of nano-formulated sitravatinib for strengthening anti-cancer effects in the absence of immunotherapy via immunogenic remodeling of the KRAS-mutant lung TME. [Display omitted] •Polymer-based nanoparticle formulation substantially enhances the anti-tumor efficiency of Sitravatinib in lung cancer.•Au@PSMA-Sit simultaneously regulates cancer cells and tumor-associated macrophages via endocytosis-induced ER stress.•Au@PSMA-Sit promotes mitochondrial fusion and glycolysis for M1 polarization in macrophages and induces ICD in cancer cells.
ISSN:1748-0132
1878-044X
DOI:10.1016/j.nantod.2023.102070