Regulatory T cells (Tregs) accumulate in the tumor microenvironment, where they suppress antitumor immunity and hinder immunotherapy efficacy. Antibody-mediated Treg depletion has emerged as a promising strategy, but its clinical translation has been hampered by incomplete mechanistic understanding, target overlap with effector T cells, and toxicity concerns. This review evaluates key determinants of Treg-depleting therapies, including the choice of target, antibody isotype and engineering, and the Fc gamma receptor landscape that governs effector function. We examine advances in next-generation antibodies targeting CTLA-4, CD25, CCR4, and CCR8, highlighting preclinical insights, early clinical outcomes, and lessons from toxicity profiles. Among next-generation approaches, Fc-optimized anti-CTLA-4 and CCR8 antibodies demonstrate selective intratumoral Treg depletion with partially improved tolerability, fueling progression into phase II/III trials. Continued refinement through novel designs, such as conditionally activated or bispecific antibodies, will be essential to balance efficacy and safety. Together, these strategies hold potential to establish Treg depletion as a viable therapeutic modality in cancer.