The immune checkpoint blockade (ICB) approach in cancer therapy involves the disruption of immune checkpoint inhibitory signals on tumor-specific CD8+ T cells, thereby reinstating the immune activity of CD8+ T cells and yielding therapeutic efficacy. However, due to the co-expression of immune checkpoint molecules, such as CTLA-4 and PD-1 on tumor-infiltrating Tregs (TI-Tregs) and conventional T cells (Tconvs), immune checkpoint inhibitors (ICIs) inadvertently amplify the immunosuppressive activity of Tregs while targeting CD8+ T cells, which contributes to the failure of immune therapy. Conventional strategies targeting Tregs, including ICI/conventional kinase and chemokine/chemokine receptor blockade, generally induce systemic Treg depletion, which triggers autoimmune diseases. Thus, achieving high selectivity and specificity in targeting TI-Tregs is of paramount importance in mitigating adverse immunologic reactions. Targeting metabolism-based TI-Tregs has been shown to enhance target precision, providing potential for the development of adjunctive immunotherapeutic strategies. This article explores the reciprocal interaction between TI-Tregs and the tumor microenvironment (TME), elucidating metabolic reprogramming, while envisioning plausible high-selectivity targets for TI-Tregs without compromising systemic immune homeostasis and immune reactivity of effector T cells.