GPR39 Suppresses Ferroptosis via the Nrf2/SLC7A11 Axis and Reduces the Sensitivity of Colorectal Cancer to Anti‐PD‐1 Immunotherapy
Background PD‐1 blockade has yet to achieve broad clinical success in colorectal cancer (CRC), with microsatellite‐stable tumors proving especially resistant. At the same time, ferroptosis has emerged as a mechanistic link between redox control in tumor cells and the antitumor immune response. GPR39 is overexpressed in CRC, but its functional role in ferroptosis and immunotherapy resistance is currently unclear. Methods GPR39 expression was analyzed in human and mouse CRC cell lines. GPR39 knockdown, with or without the ferroptosis inhibitor liproxstatin‐1, was performed to determine whether GPR39 regulates CRC cell proliferation and migration through ferroptosis. Ferroptosis was evaluated by measuring lipid peroxidation, glutathione (GSH) levels, ferrous iron (Fe2+) accumulation, and reactive oxygen species (ROS). Mechanistic involvement of the nuclear factor erythroid 2–related factor 2 (Nrf2)/solute carrier family 7 member 11 (SLC7A11) signaling axis was examined using Nrf2 overexpression. Subcutaneous implantation of MC38 cells with stable GPR39 knockdown was performed to evaluate whether GPR39 regulates tumor sensitivity to anti‐PD‐1 treatment in vivo in a ferroptosis‐dependent manner. Results GPR39 was markedly upregulated in CRC cell lines. GPR39 knockdown induced ferroptosis, characterized by increased lipid peroxidation, Fe2+ accumulation, and oxidative stress and accompanied by suppression of the Nrf2/SLC7A11 pathway. Nrf2 overexpression reversed these changes. Functionally, silencing GPR39 inhibited the proliferative and migratory capacities of CRC cells, effects that were largely rescued by liproxstatin‐1. In vivo, GPR39 knockdown significantly potentiated the antitumor activity of PD‐1 blockade, as evidenced by suppressed tumor progression accompanied by enhanced infiltration of CD8+ T cells, whereas ferroptosis inhibition abrogated these effects. Conclusion GPR39 suppresses ferroptosis in CRC via the Nrf2/SLC7A11 axis, thereby limiting PD‐1 immunotherapy efficacy.