A metal-organic nanoframework for efficient colorectal cancer immunotherapy by the cGAS-STING pathway activation and immune checkpoint blockade
Xiaodian Zhang, Hailong Tian, Yang Chen, Baichuan Liang, Edouard C. Nice, Canhua Huang, Na Xie, Shaojiang Zheng
Abstract
Immunotherapy has shown marked progress in promoting systemic anti-colorectal cancer (CRC) clinical effects. For further effectively sensitizing CRC to immunotherapy, we have engineered a pH-sensitive zeolitic imidazolate framework-8 (CS/NPs), capable of efficient cGAS-STING pathway activation and immune checkpoint blockade, by encapsulating the chemotherapeutic mitoxantrone (MTX) and immunomodulator thymus pentapeptide (TP5) and tailoring with tumor-targeting chondroitin sulfate (CS). In this nanoframework, CS endows CS/NPs with specific tumor-targeting activity and reduced systemic toxicity. Of note, the coordinated Zn2+ disrupts glycolytic processes and downregulates the expression of glucose transporter type 1 (GLUT1), thus depriving the cancer cells of their energy. Zn2+ further initiates the adenosine 5’-monophosphate activated protein kinase (AMPK) pathway, which leads to PD-L1 protein degradation and sensitizes CRC cells to immunotherapy. Moreover, the damaged double-stranded DNA during MTX treatment activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which works together with TP5 induced the proliferation and differentiation of T lymphocytes and dendritic cells to further enhance the anti-CRC immune response. Therefore, CS/NPs efficiently sensitize cells to chemotherapy and stimulate systemic antitumor immune responses both in vitro and in vivo, representing a promising strategy to increase the feasibility of CRC immunotherapy.