Tumor-infiltrating CD4⁺Foxp3⁺ regulatory T (Treg) cells express high levels of TNFR2 which mediates TNF-induced proliferation and promotes tumor progression by suppressing anti-tumor immune responses. Therefore, the blockage of TNF-TNFR2 pathway represents a strategy to eliminate tumor-infiltrating Treg activity and leads to the recovery of host immune responses against tumor. In this study, screening of in-house small-molecule library resulted in the identification of 1-aryl-1,2,3,4-tetrahydro-isoquinolines as potent inhibitors of Treg proliferation mediated by TNF-TNFR2 signaling. Moreover, in-depth analysis of structure-activity relationship (SAR) revealed that the 6,7-dimethoxylation and 1-naphthyl substitution could improve the activity. Therefore, further investigation is warranted to evaluate if 1-aryl-1,2,3,4-tetrahydro-isoquinolines could be used as adjuvants to enhance cancer immunotherapy.