Tumor-associated macrophages: untapped molecular targets to improve T cell-based immunotherapy

T cell responses are generally curtailed by suppressive mechanisms within the tumor microenvironment (TME) that prevent T cell infiltration and function. Consequently, T cell-based therapies for solid tumors have yielded limited and often non-durable clinical responses. Tumors develop a hostile TME, where tumor-associated macrophages (TAMs) that initially support T cells are converted into immune suppressive TAMs that facilitate tumor evasion from T cell control. In fact, immune suppressive TAMs represent a dominant fraction of immune cells within the TME and their presence is associated with poor prognosis and resistance to immunotherapy. Often in close contact with effector T cells, TAMs directly suppress CD8+ T cells through mechanisms involving metabolic mediators, co-signaling receptors, their ligands and/or cytokines. Here, we revisit molecular interactions behind TAM-mediated suppression of T cell responses and address the potential targeting of such molecules and pathways to re-boost anti-tumor T cell immunity. This perspective, focusing on molecular interactions between TAM and T cells, may aid the improvement of T cell-based therapies for solid tumors.