Regulatory T cell death in inflammation and tumor immunity: Focus on necroptosis, pyroptosis and ferroptosis

Regulatory T (Treg) cells are a developmentally and functionally distinct cell lineage with the suppressive capacity among CD4⁺ T cell subgroups, which contributes to immune tolerance, tissue homeostasis and regeneration. Therefore, the precise regulation of Treg cell homeostasis-achieved through a dynamic equilibrium of proliferation, survival, and death-is indispensable for a functionally competent immune system. Work over the past few decades has enhanced our understanding of the underlying molecular mechanisms regulating Treg cells abundance and function under physiological and pathological conditions. Accumulating evidence now implicates dysregulated Treg cell death in the pathogenesis of diverse diseases. For instance, Treg cells exhibit excessive death with potentially compromising immune suppression in the case of autoimmunity, allergy, transplantation and other hyperinflammatory diseases, whereas Treg cells acquire resistance to cell death in the tumor microenvironment (TME). This review systematically dissects the core mechanisms by which Treg cells are shielded from death under steady-state conditions and within the TME. Critically, we highlight how context-specific microenvironmental cues differentially modulate Treg cell death across disparate pathological settings. Cell deaths are the key regulators in maintaining Treg cell homeostasis. A nuanced understanding of these regulatory networks will inform the development of next-generation Treg-targeted therapies with improved efficacy against a broad spectrum of diseases.