# Targeting chemokine-driven metastasis in non-small cell lung cancer: Development and evaluation of chemokine nanosponges for therapy

## TL;DR

This study develops a nanosponge to target CCL20 chemokine in lung cancer, aiming to reduce metastasis and improve treatment outcomes.

## Contribution

A novel CCL20-targeting nanosponge is developed to inhibit metastasis and reprogram tumor-associated macrophages in NSCLC.

## Key findings

- CCL20 is a key chemokine driving metastasis in non-small cell lung cancer.
- The CCR6-MM@PS/R848 nanosponge effectively inhibits tumor growth and metastasis in preclinical models.
- The nanosponge promotes macrophage polarization from M2 to M1, reducing immunosuppression in the tumor microenvironment.

## Abstract

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, with a poor prognosis and high metastasis rate. Metastasis involves complex mechanisms, including chemokine secretion by tumor-associated macrophages (TAMs). Using single-cell RNA sequencing (scRNA-seq), we identified enhanced chemokine secretion by M2-type TAMs in metastatic lesions, with CCL20 emerging as a key target. We designed a CCL20-adsorbing nanosponge by engineering macrophages with high CCR6 expression and extracting their membranes. This nanosponge combines targeting ability and chemokine adsorption capacity, enabling precise treatment of high-CCL20 tumors. Additionally, we encapsulated the Toll-like receptor 7/8 agonist R848 within the CCR6-modified macrophage membrane (CCR6-MM) to polarize M2-type TAMs to the M1 phenotype, reducing CCL20 secretion and transforming the immunosuppressive tumor microenvironment. In vitro and in vivo experiments validated the therapeutic potential of the CCR6-MM and R848 combination, demonstrating biocompatibility, macrophage polarization efficacy, and dual inhibitory effects on tumor growth and metastasis. Our findings highlight the potential of chemokine nanosponges as a novel therapeutic strategy for NSCLC metastasis.

Schematic illustration of the preparation and mechanism of CCR6-MM@PS/R848 for NSCLC treatment.Image 1

•CCL20 identified as a key chemokine in NSCLC metastasis, promoting an immunosuppressive tumor microenvironment.•CCR6-MM@PS/R848 nanosponge engineered to target and adsorb CCL20, enhancing antitumor immunity.•CCR6-MM@PS/R848 effectively inhibits tumor growth and metastasis, demonstrating strong therapeutic potential in NSCLC.

CCL20 identified as a key chemokine in NSCLC metastasis, promoting an immunosuppressive tumor microenvironment.

CCR6-MM@PS/R848 nanosponge engineered to target and adsorb CCL20, enhancing antitumor immunity.

CCR6-MM@PS/R848 effectively inhibits tumor growth and metastasis, demonstrating strong therapeutic potential in NSCLC.