Multifunctional nanodrug performs sonodynamic therapy and inhibits TGF- a to boost immune response against colorectal cancer and liver metastasis

Liver metastasis is the leading cause of death in colorectal cancer. Immunotherapy using immune check-point blockade (ICB) is ineffective due to its immunological cold tumor nature. Herein, we prepared a nanodrug (NCG) encapsulating the transforming growth factor -a receptor inhibitor galunisertib (Gal) and the sonosensitizer chlorin e6 (Ce6), which was aimed to turn this type of cold tumor into a hot one to promote the ICB-based immunotherapy against it. After delivery to the tumor, NCG under ultrasonic irradiation generated reactive oxygen species causing tumor immunogenic cell death and releasing im-munostimulatory signals such as calreticulin and HMGB1, which increased tumor immunogenicity and activated the innate T lymphocyte immune response. Moreover, NCG responded to the acidic microenvi-ronment and released Gal, inhibiting phosphorylation and inducing immunosuppressive Smad2/3 signal-ing. Consequently, the differentiation of MDSCs was inhibited, M1-like polarization of tumor-associated macrophages was induced, and the immunosuppressive barrier of tumor-associated fibroblasts was de-stroyed to increase the infiltration of effector T cells, which reversed the immunosuppression of the tu-mor microenvironment and improved the therapeutic efficacy of anti-PD-L1 antibodies. Notably, in the liver metastasis mouse model, combination therapy using NCG ( + ) and aPD-L1 inhibited the growth of colon cancer liver metastasis, manifesting potential in treating this popular yet intractable malignancy.Only a limited number of patients with colorectal cancer and liver metastasis can benefit from immune checkpoint blockade therapy, as most of them are microsatellite stable, immunologically cold tumors. In-terestingly, there is compelling evidence that sonodynamic therapy (SDT) can convert immunosuppressed cold tumors into hot ones, trigger tumor immunogenic cell death non-invasively, and boost cytotoxic T cells infiltration. However, its therapeutic efficacy is constrained by the abundance of transforming growth factor -a (TGF-a) cytokines in the tumor microenvironment. Here, we reported a TGF-a-targeted inhibitory nanodrug that improved SDT in colon cancer and liver metastasis, reversed the immunosup-pressive tumor microenvironment and boosted the immune response to anti-PD-L1 therapy in this cancer. It demonstrated the potential to cure this prevalent but incurable malignancy.(c) 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.