In pediatric brain tumors medulloblastoma (MB) and diffuse midline glioma (DMG), tumor-associated myeloid cells (TAMs) support malignant progression by secreting paracrine growth factors and suppressing local immune function. We studied the potential for reversing this cancer-supportive phenotype by stimulating TAM pathogen receptors using ResiPOx, a brain-permeant, polyoxazoline nanoparticle formulation of the TLR7/8 agonist resiquimod. ResiPOx showed blood-brain barrier penetration and anti-tumor efficacy, extending progression-free survival (PFS) in mice with MB and DMG. Integrated cellular and molecular analysis including scRNA-seq showed that ResiPOx expanded TAM populations and reprogrammed TAMs toward anti-tumoral states, blocking paracrine IGF1 signaling and inducing local cytokine signaling and phagocytosis of tumor cells. In rhesus macaques, systemic ResiPOx was well tolerated and induced brain transcriptional patterns that resembled ResiPOx responses in DMG and MB mouse models, indicating effects in non-human primates that highlight translational potential. Our data show that ResiPOx reshapes the brain tumor microenvironment to inhibit tumor growth. As a systemically administered, brain penetrant immunomodulator, ResiPOx is able to reach multifocal and unresectable brain tumors, including MB and DMG.