TNF receptor-associated factor 6 sensitizes prostate cancer cells to CD8+ T cell-mediated ferroptosis via Lipocalin 2 degradation.

Prostate cancer remains a significant therapeutic challenge in male urologic oncology. Characterized by an immunosuppressive microenvironment, it is commonly described as an immunologically "cold" tumor. This study elucidates the role of TNF receptor-associated factor 6 (TRAF6) within the immune landscape of prostate cancer. We observed marked downregulation of TRAF6 in both patient-derived tissues and cultured prostate cancer cell lines. Functional assays demonstrated that TRAF6 upregulation robustly suppresses cancer cell proliferation and migration. Mechanistically, we discovered that TRAF6 sensitizes prostate cancer cells to CD8+ T cell-mediated ferroptosis by targeting Lipocalin 2 (LCN2) for proteasomal degradation. The anti-tumor effects of TRAF6 overexpression were reversed upon LCN2 restoration. Further analyses showed that TRAF6 promotes LCN2 ubiquitination and subsequent proteasomal degradation. Our results reveal a previously unrecognized pathway by which TRAF6 modulates tumor cell susceptibility to CD8+ T cell-associated ferroptosis, highlighting the translational potential of targeting the TRAF6-LCN2 signaling axis in prostate cancer therapy.