# Functionalized Biomaterials in the Investigation of the Effects of Fluid Shear Forces in the Immune Regulation of Cancer Progression and Metastasis

## TL;DR

This paper reviews how fluid shear stress affects cancer progression and immune responses using 3D in vitro models and bioreactors.

## Contribution

The paper introduces novel 3D cancer models and bioreactors to study fluid shear stress effects on immune regulation and cancer.

## Key findings

- 3D cancer cultures with T cells mimic cell-matrix interactions and immune responses.
- Flow perfusion bioreactors with biosensors enable real-time monitoring of immune cell activation.
- Combining CCL19 pDNA and PD-1/PD-L1 inhibitors improves antitumor immunity in modified nanocarriers.

## Abstract

As cancer mortality rates rise globally, malignancies have become the second leading cause of death. Recently, efforts have been made to understand the impact of the tumor microenvironment that involves fluid shear forces. Biomechanical stimulation, which uses shear stress to activate mechanosensitive ion channels, e.g., Piezo1, increases calcium influx into the intracellular space and activates T cells. Novel 3D cancer cultures with T cells have been proposed. Such models use cell/scaffold constructs to recapitulate interactions between cells and the extracellular matrix. In addition, flow perfusion bioreactors investigate the impact of fluid shear forces on immune and/or cancer cells. These bioreactors have biosensors that allow monitoring of immune cell activation. Furthermore, they provide a biomimetic environment for the study of the interaction of T cells and cancer cells. Hence, immune checkpoint inhibitors have demonstrated immunotherapeutic efficacy, but a single-target blockade has often proved insufficient. Co-delivery of CCL19 pDNA and the PD-1/PD-L1 interaction inhibitor BMS-1 using RGD-modified nanocarriers targeting tumor integrins enhanced local antitumor immunity. This review highlights recent insights into how fluid shear stress (FSS) regulates cancer progression and immune responses in three-dimensional in vitro models, with a focus on bioreactors and the surface modification of scaffold materials.