Role of elevation of glycolysis in tumor-associated macrophages in glioblastoma immune evasion and therapeutic implications

Abstract Glioblastoma is a highly aggressive brain cancer with significant mortality, primarily due to CD8+ T cell deficiency, which obstructs effective treatment outcomes. The dysfunction and exhaustion of CD8+ T cells are strongly linked to tumor-associated macrophages (TAMs), which, when exhibiting heightened glycolysis, secrete interleukin-10 and express programmed death ligand 1, both of which suppress CD8+ T cell function. This is under the control of cytokines and growth factors in the glioblastoma tumor microenvironment which activate multiple signaling pathways in TAMs. Moreover, TAMs can increase the aggressiveness of cancer cells by enhancing the activation of oncogenic signaling pathways. Understanding the mechanisms of the roles of glycolysis in TAM development and function as well as the regulation of glycolysis by various signaling pathways has substantial therapeutic implications. In this review, we summarize the most recent progress in TAMs, focusing on glycolysis and examine their interactions with both CD8+ T cells and cancer cells, and their control by signaling pathways. We also discuss in detail the potential therapeutic strategies prompted by new discoveries regarding glycolysis and signaling pathways in TAMs.