THE ROLE OF TUMOR-ASSOCIATED M2 MACROPHAGES IN OSTEOSARCOMA GENESIS: INVASIVE MECHANISMS

Abstract

Innate immune responses are tightly regulated by various cell types, with macrophages playing a central role due to their remarkable functional plasticity. These cells can polarize into different phenotypes in response to environmental stimuli, forming a functional spectrum ranging from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. M1 macrophages are induced by Th1 cytokines and microbial components such as LPS and TLR agonists. They are characterized by the production of inflammatory cytokines like IL-6 and by the high expression of major histocompatibility complex molecules (MHC I and II), which are essential for antitumor immunity. Conversely, M2 macrophages respond to a variety of stimuli and are subdivided into M2a, M2b, M2c, and M2d subtypes, each associated with functions such as inflammation resolution, tissue repair, and angiogenesis. Despite their functional differences, all M2 subtypes share immunosuppressive features and are commonly associated with tumor progression. Among them, tumor-associated macrophages (TAMs) are predominantly of the M2 type and are highly abundant within the tumor microenvironment (TME), where they promote immune evasion, tumor proliferation, angiogenesis, and therapeutic resistance. One key immunosuppressive mechanism used by TAMs is the expression of Arginase-1, an enzyme that inhibits T cell-mediated immune responses, thereby facilitating tumor immune evasion. Notably, the distinction between M1 and M2 macrophages is not absolute but represents a dynamic and reversible continuum of activation states that can shift according to changes in the local microenvironment. Understanding the mechanisms underlying macrophage plasticity and function in the TME holds significant clinical potential. Therapeutic strategies aimed at reprogramming TAMs from an M2 to an M1 phenotype, or targeting key molecules such as Arginase-1, offer promising avenues for restoring T cell activity and enhancing antitumor immune responses. Therefore, the findings discussed provide valuable insights into tumor immunology and highlight potential targets for the development of more effective and personalized immunotherapies for cancer treatment.