Development of a novel peptide targeting GPR81 to suppress adipocyte-mediated tumor progression

GPR81, initially discovered in adipocytes, has been found to suppress lipolysis when activated. However, the current small molecules that target GPR81 carry the risk of off-target effects, and their impact on tumor progression remains uncertain. Here, we utilized phage display technology to screen a GPR81-targeting peptide named 7w-2 and proceeded to demonstrate its bioactivity. Although 7w-2 did not affect the proliferation of tumor cells, it effectively reduced adipocyte catabolism in vitro, consequently restraining the proliferation of co-cultured tumor cells. Furthermore, our findings revealed that 7w-2 could inhibit lipolysis in vivo, leading to a significant impediment in tumor growth and metastasis in the 4T1 murine tumor model. Additionally, 7w-2 exhibited the ability to significantly elevate the proportion and functionality of CD8+ T cells. Our study introduces 7w-2 as the first peptide targeting GPR81, shedding light on its potential role in adipocytes in suppressing tumor progression.