Targeting the stimulatory immune checkpoint glucocorticoid-induced TNFR-related protein (GITR) using agonistic monoclonal antibodies (mAbs) is a promising strategy for cancer immunotherapy that activates effector T cells and eliminates regulatory T cells (Treg). The pre-clinical anti-tumor activity of GITR mAbs depends on activating Fcγ receptors (FcγRs). However, the human Fc-FcgR interactions in the activity of GITR mAbs have not been comprehensively investigated. To this end, we employed Fc protein and glycan engineering to modify the FcγR interactions of anti-GITR human mAbs and characterized them in humanized FcgR mice. We identified an Fc-optimized human IgG scaffold that enhances anti-tumor efficacy through multiple FcgR-mediated mechanisms, including Treg depletion and mutual engagement and activation of CD4+ T cells and dendritic cells, leading to anti-tumor cytotoxicity of CD4+ T cells and enhanced CD8+ T cell activity. Our findings suggest a strategy to optimize human GITR mAbs, harnessing beneficial immune pathways to improve their therapeutic potential.