Carrier-Free Small-Molecule Drug Nanoassembly Elicits Chemoimmunotherapy via Co-inhibition of PD-L1/mTOR

Area of Science:

• Oncology
• Nanomedicine
• Immunotherapy

Background:

• Tumor growth and progression are driven by cytokines in the tumor microenvironment.
• Effective co-inhibition strategies for enhanced cancer therapy are limited.
• Targeting mTOR and PD-L1 simultaneously offers therapeutic potential.

Purpose of the Study:

• To construct a nanoassembly for co-inhibition of mTOR and PD-L1.
• To evaluate the therapeutic efficacy of the nanoassembly in vitro and in vivo.
• To explore the potential of this nanoassembly in cancer immunotherapy.

Main Methods:

• Assembly of small-molecule inhibitors (Rapa and (+)-JQ1) with NIR dye (IR783) into a stable nanoassembly.
• Assessment of PD-L1 and PKM2 downregulation by the nanoassembly.
• Evaluation of cancer cell apoptosis and in vivo tumor growth inhibition and metastasis.

Main Results:

• The JQ1/Rapa-IR783 nanoassembly demonstrated controllable particle size and stability.
• Efficient downregulation of PD-L1 and PKM2 levels was observed.
• Combined Rapa and (+)-JQ1 treatment significantly enhanced cancer cell apoptosis.
• In vivo studies showed inhibition of primary tumor growth and reduced pulmonary metastasis.

Conclusions:

• The developed nanoassembly effectively co-delivers Rapa and (+)-JQ1 for simultaneous mTOR and PD-L1 inhibition.
• This strategy reinvigorates the immune system, leading to enhanced cancer immunotherapy.
• Nanoassemblies represent a promising platform for codelivery of immunomodulators in cancer treatment.