# How do tumor-associated neutrophils regulate the microenvironmental landscape of brain tumors: Delivery of nano-particles through BBB

## TL;DR

This study explores how neutrophils influence brain tumor growth and proposes new therapies using mathematical models and nanoparticle delivery to improve treatment outcomes.

## Contribution

A new mathematical model and therapeutic strategies using neutrophils and nanoparticles to control glioblastoma.

## Key findings

- TANs regulate tumor growth through phenotypic switches between N1 and N2 types.
- Neutrophil-mediated nanoparticle delivery and combination therapy can control glioma infiltration.
- The approach may reduce cognitive impairment and improve anti-tumor efficacy.

## Abstract

Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with the very poor survival and high recurrence rate. Tumor-associated neutrophils (TANs) play a pivotal role in regulation of the tumor microenvironment. In this study, we developed a new mathematical model of the critical GBM-TAN interaction in the heterogeneous brain tissue. The model reveals that the dual and complex role of TANs (either anti-tumorigenic N1 and the pro-tumorigenic N2 type) regulates the phenotypic trajectory of the evolution of tumor growth and the invasive patterns in white and gray matter via mediators such as IFN-β and TGF-β. We investigated the effect of normalizing the immune environment on glioma growth by applying a therapeutic antibody and developed several strategies for eradication of tumor cells by neutrophil-mediated transport of nanoparticles. We also developed a strategy of combination therapy (surgery + Trojan neutrophils) for effective control of the infiltration of the glioma cells in one hemisphere before crossing the corpus callosum (CC) in order to prevent recurrence in the other hemisphere. This alternative approach compared to the extended resection of the glioma including CC or butterfly GBM may provide the greater anti-tumor efficacy and reduce side effects such as cognitive impairment.

Glioblastoma (GBM), the most aggressive form of brain cancer, is characterized by rapid growth and aggressive invasion even after surgery, leading to very poor survival. While neutrophils circulating in the blood are an important part of the immune system as the first line of defense against cancer, tumor-associated neutrophils (TANs) play a dual role in regulation of the tumor microenvironment. We used mathematical models to investigate the critical GBM-TAN interaction in the heterogeneous brain tissue. The model showed the complex phenotypic switches between N1 and N2 phenotypes in the evolution of tumor growth and the invasive patterns under biophysical conditions in white and gray matter via regulation of biochemical mediators. In this study, we developed several strategies for killing GBM cells by a therapeutic antibody against N2 TANs and neutrophil-mediated transport of anti-cancer nanoparticles. We also illustrated how a combination therapy (surgery + Trojan neutrophils) effectively control glioma infiltration through the corpus callosum, preventing regrowth of GBM in the contralateral hemisphere. This new approach may provide greater anti-tumor efficacy and reduce side effects such as cognitive impairment as a result of damage to normal brain tissue.