Macrophages: new and innovative strategies for the treatment of different pathologies

Abstract

Introduction: Macrophages are cells of the innate immune system with high plasticity that can transition from a pro-inflammatory and antitumour phenotype (M1) to an anti-inflammatory and pro-resolving one (M2). This versatility makes them attractive therapeutic targets for treating various pathologies. Objective: In this narrative review, we describe and classify updated methodologies that enable targeted intervention on the molecular pathways sustaining a pathological immunophenotype, redirecting the macrophage response towards a beneficial state depending on the disease. Methodology: To this end, an exhaustive search was conducted across databases such as Google Scholar, PubMed, SciELO, and ScienceDirect/Scopus, utilizing full-text filters and advanced search strategies with terms such as "Macrophage Polarization". A total of 22 preclinical empirical articles published in the last 7 years were selected from 11,400 identified studies. Results: We grouped the studies into five types of strategies for modulating the macrophage phenotype. Physico-chemical strategies repolarize macrophages by modifying the microenvironment and oxidative stress through stimuli such as phototherapy and ultrasound. Enzymatic strategies inhibit key enzymes or regulate their metabolites. Gene therapy strategies silence genes using small interfering RNA (siRNA) or targeted exosomes. Finally, microbial and plant-derived immunomodulators modify metabolism and inhibit or activate intracellular signaling pathways. Conclusion: This review highlights recent preclinical advances revealing how controlling redox balance, hypoxia, and metabolic pathways allows for the repolarization of pathological niches. Despite these discoveries, tissue heterogeneity and safety remain the primary barriers to their translation into clinical practice.