TAMing the tumor: targeting immune inhibitory receptors on tumor-associated macrophages in pediatric brain tumors - an emerging immunotherapy strategy.

Abstract

Brain tumors are the most common solid tumors in children. Despite recent advancements in cancer survival, the prognosis for high-grade pediatric brain tumors remains poor, with treatments resulting in severe long-term side effects. Over the last decade, immune checkpoint blockade (ICB) has emerged as a promising treatment strategy, with success across various tumor types, particularly in adult malignancies. However, its efficacy in pediatric brain tumors has been limited, which can be attributed to the unique characteristics of the brain tumor microenvironment (TME), including a low mutational burden, restricted T cell infiltration, and immunosuppressive milieu. Importantly, clinically approved ICBs primarily target T cell-associated pathways, thereby neglecting other dominant immune populations within the TME.Among these, tumor-associated macrophages (TAMs) often represent the most abundant immune cell compartment within pediatric brain tumors. TAMs consist of resident microglia and infiltrating bone marrow-derived macrophages and play a central role in establishing and maintaining an immunosuppressive environment. They promote tumor progression, suppress cytotoxic T cell activity, and contribute to therapeutic resistance. However, they are highly heterogeneous, and their phenotype and functions are regulated by the surrounding TME. This intrinsic plasticity makes them promising therapeutic targets: rather than solely attempting to enhance T cell activity, reprogramming TAMs may fundamentally remodel the immune landscape of pediatric brain tumors.In this context, immune inhibitory receptors emerge as critical regulators of TAM function. While traditionally studied in T cells, inhibitory receptors expressed on macrophages influence phagocytosis, cytokine production, antigen presentation, and polarization states. Emerging preclinical evidence indicates that targeting inhibitory receptors on TAMs can shift macrophages from suppressive toward pro-inflammatory phenotypes, enhance phagocytosis, and improve survival in brain tumor models. Nevertheless, the expression patterns and functional consequences of these receptors in pediatric brain TAMs remain incompletely characterized.In this review, we examine the role of immune inhibitory receptors on TAMs in pediatric brain tumors and discuss how targeting these pathways may reprogram the TME, enhance antitumor immunity, and provide new therapeutic avenues for this challenging group of malignancies. Unlike most pediatric brain tumor immunotherapy reviews, this review specifically evaluates myeloid-targeted inhibitory receptor pathways in the pediatric brain tumor context.