Spatial organization of mediated-macrophage chemoprotective niches in solid tumors: A mathematical analysis

¹ Univ.Grenoble Alpes, Inserm U1209, CNRS UMR5309, Institute for Advanced Biosciences, Team Mechanobiology, Immunity and Cancer, 38000 Grenoble, France
² Univ.Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, 38000 Grenoble, France

^* Corresponding author: arnaud.millet@inserm.fr

Received: 22 November 2024
Accepted: 25 March 2025

Abstract

Acquired resistance is one of the major causes of failure of standard therapies in cancer patients. Chemotherapeutic agents are still widely used and the understanding of the mechanisms leading to secondary resistance to these molecules are still puzzling. Recently, the role of the tumor immune microenvironment has been recognized. Among the cells potentially involved, macrophages seem to be the perfect culprits. In a previous work, we have shown that hypoxic macrophages are able to provide strong protection against 5-fluorouracil, a first-line chemotherapeutic agent in digestive cancers. In the present work, we use mathematical modeling to explore the spatiotemporal aspects of the treatment-induced organization of the tumor environment. Based on analytical and numerical analysis, we propose that macrophage-driven protection against chemotherapy under treatment does not rely solely on biochemical degradation, but is enhanced by the emergence of spatially structured chemotherapeutic protective niches. This work paves the way for the development of new therapeutic strategies that rely on targeting the spatial organization of tumors as a way to control treatment resistance.