Macrophage metabolic reprogramming as a therapeutic approach for cancer and muscular dystrophy

Macrophages have been implicated in the pathogenesis of cancer and chronic degenerative diseases, such as Duchenne Muscular Dystrophy (DMD). In the last years, metabolic reprogramming of macrophages has emerged as a promising therapeutic approach to treat diseases with high macrophage infiltration, as alterations in their metabolism have been shown to reshape their immune function and phenotype. In the context of cancer, several reports have shown that glycolysis-derived lactate released by tumor cells modulates tumor-associated macrophages (TAMs) into a pro-tumoral phenotype. This contributes to an immunosuppressive tumor microenvironment (TME) that decreases cytotoxic T-cell responses. In this sense, our group previously inhibited CD147, the chaperone of the lactate transporters MCT1/4, in cancer cells to reduce their activity and lactate export. However, its impact in TAMs and in the TME is yet to be elucidated. In addition to targeting tumor-derived lactate transport, the host lab recently demonstrated the deletion of GLUD1 in macrophages shifts their metabolism towards glycolysis, a characteristic of an M1/ anti-tumor phenotype, and fosters glutamine synthesis and secretion, overcoming the shortage of this amino-acid in the TME that impairs T cell activation and function. Moreover, in muscles, the macrophagic inhibition of GLUD1 and the consequent increase in extracellular glutamine levels showed to help satellite cells to proliferate, properly differentiate and improve muscle regeneration. Therefore, we hypothesize the metabolic re-education of TAMs, via tumoral CD147 or macrophagic GLUD1 deletion, may alleviate the immunosuppressive features of TME and reinforce the therapeutic efficacy of anti-PD-1 immunotherapies. Moreover, we strongly believe the inhibition of GLUD1 in macrophages populating muscle tissue may improve the regenerative potential of dystrophic muscles. Thus, the main aim of this research project is to shed light on the biological mechanisms by which tumoral CD147 or macrophage GLUD1 expression modulates macrophage polarization status and TME immunosuppression, and provide evidence for CD147 and GLUD1 as effective targets to promote anti-tumor immune response and prevent muscle degeneration.