Xiancai Zhong

Xiancai Zhong, Hongmin Wu, Hye-Kyung Na. J Cancer Prev 2026;31:195-213. https://doi.org/10.15430/JCP.26.050

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Nuclear receptor coactivator 2 (Ncoa2) is a member of the Ncoa family of coactivators, and we previously showed that Ncoa2 regulates the differentiation of induced regulatory T cells. However, it remains unknown if Ncoa2 plays a role in CD8+ T-cell function. Here, we show that Ncoa2 promotes CD8+ T cell–mediated immune responses against tumors by stimulating T-cell activation via upregulating PGC-1α expression to enhance mitochondrial function. Mice deficient in Ncoa2 in T cells (Ncoa2fl/fl/CD4Cre) displayed defective immune responses against implanted MC38 tumors, which associated with significantly reduced tumor-infiltrating CD8+ T cells and decreased IFNγ production. Consistently, CD8+ T cells from Ncoa2fl/fl/CD4Cre mice failed to reject tumors after adoptive transfer into Rag1−/− mice. Further, in response to TCR stimulation, Ncoa2fl/fl/CD4Cre CD8+ T cells failed to increase mitochondrial mass, showed impaired oxidative phosphorylation, and had lower expression of PGC-1α, a master regulator of mitochondrial biogenesis and function. Mechanically, T-cell activation–induced phosphorylation of CREB triggered the recruitment of Ncoa2 to bind to enhancers, thus, stimulating PGC-1α expression. Forced expression of PGC-1α in Ncoa2fl/fl/CD4Cre CD8+ T cells restored mitochondrial function, T-cell activation, IFNγ production, and antitumor immunity. This work informs the development of Ncoa2-based therapies that modulate CD8+ T cell–mediated antitumor immune responses.

Recurrent somatic mutations in spliceosome factor 3b subunit 1 (SF3B1) are identified in hematopoietic malignancies, with SF3B1-K700E being the most common one. Here, we show that regulatory T cell (T _reg )–specific expression of SF3B1-K700E ( Sf3b1 ^K700Efl/+ /Foxp3 ^YFP-Cre ) results in spontaneous autoimmune phenotypes. CD4 ⁺ T cells from Sf3b1 ^K700Efl/+ /Foxp3 ^YFP-Cre mice display defective T _reg differentiation and inhibitory function, which is demonstrated by failed prevention of adoptive transfer colitis by Sf3b1 ^K700Efl/+ /Foxp3 ^YFP-Cre T _regs . Mechanically, SF3B1-K700E induces an aberrant splicing event that results in reduced expression of a cell proliferation regulator Anapc13 due to the insertion of a 231–base pair DNA fragment to the 5′ untranslated region. Forced expression of the Anapc13 gene restores the differentiation and ability of Sf3b1 ^K700Efl/+ /Foxp3 ^YFP-Cre T _regs to prevent adoptive transfer colitis. In addition, acute myeloid leukemia grows faster in aged, but not young, Sf3b1 ^K700Efl/+ /Foxp3 ^YFP-Cre mice compared to Foxp3 ^YFP-Cre mice. Our results highlight the impact of cancer-associated SF3B1 mutation on immune responses, which affect cancer development.

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Nuclear receptor coactivator 2 (Ncoa2) is a member of the Ncoa family of co-activators, and we previously showed that Ncoa2 regulates the differentiation of induced regulatory T cells. However, it remains unknown if Ncoa2 plays a role in CD8+ T-cell function. Here, we show that Ncoa2 promotes CD8+ T cell-mediated immune responses against tumors by stimulating T-cell activation via upregulating PGC-1α expression to enhance mitochondrial function. Mice deficient in Ncoa2 in T cells (Ncoa2fl/fl/CD4Cre) displayed defective immune responses against implanted MC38 tumors, which associated with significantly reduced tumor-infiltrating CD8+ T cells and decreased IFNγ production. Consistently, CD8+ T cells from Ncoa2fl/fl/CD4Cre mice failed to reject tumors after adoptive transfer into Rag1-/- mice. Further, in response to TCR stimulation, Ncoa2fl/fl/CD4Cre CD8+ T cells failed to increase mitochondrial mass, showed impaired oxidative phosphorylation, and had lower expression of PGC-1α, a master regulator of mitochondrial biogenesis and function. Mechanically, T cell activation-induced phosphorylation of CREB triggered the recruitment of Ncoa2 to bind to enhancers, thus, stimulating PGC-1α expression. Forced expression of PGC-1α in Ncoa2fl/fl/CD4Cre CD8+ T cells restored mitochondrial function, T-cell activation, IFNγ production, and anti-tumor immunity. This work informs the development of Ncoa2-based therapies that modulate CD8+ T cell-mediated anti-tumor immune responses.

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Th17 cells are a subset of IL-17-expressing CD4⁺ T helper cells and play a predominant role in the pathogenesis of autoimmune diseases such as multiple sclerosis and psoriasis. Th17 cells sustain their activation and effector functions primarily through a metabolic profile characterized by high glycolytic and oxidative metabolism. Both glycolysis and OXPHOs can affect cellular redox status, and vice versa. Nrf2, a master regulator of redox homeostasis, plays a pivotal role in oxidative stress regulation and influences immune cell function. This chapter summarizes the recent advances in the understanding of redox regulation in Th17 cells and explores the therapeutic potential of targeting Nrf2 in Th17-dependent autoimmune diseases. Overall, targeting Nrf2 holds considerable promise as a novel therapeutic paradigm for Th17-dependent autoimmune diseases, offering new avenues for precision medicine and improved disease outcomes.