Novel Cocktail Therapy Based on a Nanocarrier with an Efficient Transcytosis Property Reverses the Dynamically Deteriorating Tumor Microenvironment for Enhanced Immunotherapy

The immune checkpoint blockade (ICB) faces a low response rate in clinical cancer treatment. Chemotherapy could enhance the response rate of the ICB, but patients would suffer from side effects. The off-target toxicity could be reduced by loading the chemotherapeutic agent through nanocarriers. There-fore, we developed a polymeric carrier for doxorubicin (DOX) loading to form DOX nanoparticles (DOX NPs), which were spatiotemporally responsive to the tumor microenvironment (TME). DOX NPs had an efficient transcytosis property for deep tumor infiltration and sustained drug release ability. Unfortunately, a binary therapy of DOX NPs and ICB induces tumor adaptive resistance and causes dynamic deterioration of the TME. We propose for the first time that TGF-beta 1 is a major cause of tumor adaptive resistance and developed an immune cocktail therapy containing DOX NPs, ICB, and TGF-beta 1 gene silencing nanoparticles. This therapy successfully overcame tumor adaptive resistance by reversing the immunosuppressive TME and achieved enhanced tumor treatment efficiency.

Automated summary

The immune checkpoint blockade (ICB) has a low response rate in clinical cancer treatment. Chemotherapy can enhance the response rate of the ICB, but it leads to side effects. Loading chemotherapy drugs through nanocarriers can reduce off-target toxicity. In this study, researchers developed doxorubicin (DOX) nanoparticles (DOX NPs) loaded in a polymeric carrier that was responsive to the tumor microenvironment (TME). However, a combination therapy of DOX NPs and ICB induced tumor adaptive resistance, which was found to be caused by TGF-beta 1. To overcome this resistance, an immune cocktail therapy containing DOX NPs, ICB, and TGF-beta 1 gene silencing nanoparticles was developed, successfully reversing the immunosuppressive TME and improving tumor treatment efficiency.