Inflammation-Regulated Nanodrug Sensitizes Hepatocellular Carcinoma to Checkpoint Blockade Therapy by Reprogramming the Tumor Microenvironment

Abstract

Immune checkpoint blockade (ICB) utilizing programmed death ligand-1 (PD-L1) antibody is a promising treatment strategy in solid tumors. However, in fact, more than half of hepatocellular carcinoma (HCC) patients are unresponsive to PD-L1-based ICB treatment due to multiple immune evasion mechanisms such as the hyperactivation of inflammation pathway, excessive tumor-associated macrophages (TAMs) infiltration, and insufficient infiltration of T cells. Herein, an inflammation-regulated nanodrug was designed to codeliver NF-κB inhibitor curcumin and PD-L1 antibody to reprogram the tumor microenvironment (TME) and activate antitumor immunity. The nanodrug accumulated in TME by an enhanced permeability and retention effect, where it left antibody to block PD-L1 on the membrane of tumor cells and TAMs due to pH-responsiveness. Simultaneously, a new curcumin-encapsulated nanodrug was generated, which was easily absorbed by either tumor cells or TAMs to inhibit the nuclear factor kappa-B (NF-κB) signal and related immunosuppressive genes. The inflammation-regulated nanodrug possessed good biocompatibility. Simultaneously, it reprogrammed TME effectively and exhibited an effective anticancer effect in immunocompetent mice. Overall, this study provided a potent strategy to improve the efficiency of ICB-based treatment for HCC.

Interface‐Engineered 2D Heterojunction with Photoelectric Dual Gain: Mxene@MOF‐Enhanced SPR Spectroscopy for Direct Sensing of Exosomes

“…PD‐L1 has been reported as a potential cancer biomarker for the diagnosis of cancer progression and metastasis. [ 54 ] During the development of cancer, cancer cells secrete more exosomes, which show significant changes in serum. [ 55 ] And PD‐L1 protein is usually highly expressed on the surface of exosomes, so Exo‐PD‐L1 can be used as a disease marker for early diagnosis of various cancers.…”

Tunable Au@SiO2/Au Film Metasurface as Surface Plasmon Resonance Enhancer for Direct and Ultrasensitive Detection of Exosomes

“…Programmed death ligand 1 (PD-L1) is a prominent molecule employed by tumor cells to engage T-cell immune checkpoints. 1 It has been established that PD-L1-positive (PD-L1 + ) exosomes hold potential as predictors of the clinical outcome of anti-programmed cell death protein 1 (anti-PD-1) therapy and serve as biomarkers for tumor burden. 2 Therefore, the detection of PD-L1 + exosomes is crucial for clinical diagnosis and precision medicine.…”