Bap1-mediated deubiquitination governs Treg immune tolerance and anti-tumor immunity via ferroptosis control
核心洞察
Bap1 (搜索), a histone H2A deubiquitinase and known tumor suppressor, is essential for the homeostasis and suppressive function of regulatory T cells (Tregs).
Loss of Bap1 (搜索) disrupts Treg immune tolerance and enhances anti-tumor immunity by modulating ferroptosis, a regulated cell death pathway linked to lipid metabolism.
The findings connect Bap1 (搜索)'s metabolic regulation of ferroptosis to Treg stability, offering a potential mechanistic basis for targeting Tregs in cancer immunotherapy.
Bap1 (搜索) (BRCA1 (搜索)-associated protein 1), a ubiquitin hydrolase and histone H2A deubiquitinase, determines immune tolerance and anti-tumor immunity by controlling ferroptosis in regulatory T cells (Tregs), according to new research. The work establishes a mechanistic link between Bap1-mediated deubiquitination, Treg homeostasis, and the metabolic regulation of ferroptosis, a regulated cell death pathway.
Bap1 (搜索) was first identified as a novel ubiquitin hydrolase that binds the BRCA1 (搜索) RING finger and enhances BRCA1-mediated cell growth suppression. It functions within the Polycomb repressive deubiquitinase complex (PR-DUB), where it counteracts widespread H2AK119ub1 deposition and chromatin condensation, thereby enhancing Polycomb repression. As a tumor suppressor, Bap1 has been implicated in diverse processes, including the regulation of cell proliferation, metabolism, and myeloid transformation. Loss of the tumor suppressor BAP1 has been shown to cause myeloid transformation, and germline BAP1 mutations induce a Warburg effect, linking Bap1 to metabolic reprogramming.
The new findings center on the role of Bap1 (搜索) in regulatory T cells, which are critical mediators of immune tolerance and suppressors of anti-tumor immunity. Tregs in the tumor microenvironment represent a major barrier to effective cancer immunotherapy, and tumor-infiltrating regulatory T cells have been identified as targets of cancer immunotherapy. Prior work demonstrated that the glutathione peroxidase Gpx4 (搜索) prevents lipid peroxidation and ferroptosis to sustain Treg cell activation and suppression of antitumor immunity, establishing ferroptosis control as essential for Treg function.
Bap1 (搜索)-mediated deubiquitination is now shown to determine immune tolerance and anti-tumor immunity through this ferroptosis axis. Ferroptosis is a regulated cell death nexus linking metabolism, redox biology, and disease, and its metabolic underpinnings are tightly coupled to lipid metabolism. Bap1 has previously been shown to link metabolic regulation of ferroptosis to tumor suppression, and BAP1 has been described as a regulator of cell metabolism. The intersection of Bap1 activity with ferroptosis susceptibility in immune cells provides a mechanistic framework for how this deubiquitinase governs Treg stability and, consequently, the balance between immune tolerance and anti-tumor immunity.
The clinical relevance of Bap1 (搜索) extends to human cancer. BAP1 mutations are associated with distinct tumor entities, including mesothelioma (搜索), where germline BAP1 mutation-associated mesothelioma represents a biologically and clinically distinct entity. Studies have characterized the immune composition and immunotherapy outcomes of mesothelioma with BAP1, CDKN2A, MTAP, and NF2 alterations, underscoring the potential for Bap1 status to inform immunotherapeutic strategies.
The study highlights the convergence of epigenetic regulation, Treg biology, and ferroptosis metabolism. By demonstrating that Bap1 (搜索)-mediated deubiquitination is required for Treg-mediated immune tolerance and that its disruption enhances anti-tumor immunity, the research identifies Bap1 as a candidate node for therapeutic intervention aimed at overcoming Treg-driven immunosuppression in cancer.