Metabolic Fitness of NAC1-Deficient Regulatory T Cells in the Tumor Microenvironment Fuels Tumor Growth

Anil Kumar; Jugal Das; Hao-Yun Peng; Liqing Wang; Darby Ballard; Yijie Ren; Xiaofang Xiong; Xingcong Ren; Jin-Ming Yang; Paul de Figueiredo; Jianxun Song

doi:10.1172/jci.insight.186000

Metabolic Fitness of NAC1-Deficient Regulatory T Cells in the Tumor Microenvironment Fuels Tumor Growth

Anil Kumar,¹ Jugal Das,¹ Hao-Yun Peng,¹ Liqing Wang,¹ Darby Ballard,¹ Yijie Ren,¹ Xiaofang Xiong,¹ Xingcong Ren,² Jin-Ming Yang,² Paul de Figueiredo,³ and Jianxun Song¹

Published January 7, 2025 - More info

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Abstract

The nucleus accumbens-associated protein-1 (NAC1) has recently emerged as a pivotal factor in oncogenesis by promoting glycolysis. Deletion of NAC1 in regulatory T cells (Tregs) has been shown to enhance FoxP3 stability, a suppressor of glycolysis. This study delves into the intriguing dual role of NAC1, uncovering that Tregs-specific deletion of NAC1 fosters metabolic fitness in Tregs, thereby promoting tumorigenesis. Our results unveil that NAC1-deficient Tregs exhibit prolonged survival and heightened function, particularly in acidic environments. Mechanistically, we find that NAC1-deficient Tregs adapt to adverse conditions by upregulating FoxP3 expression, engaging in CD36-mediated lipid metabolism, and enhancing PGC-1α-regulated mitochondrial function. In mouse tumor xenograft models, NAC1-deficient mice demonstrate increased susceptibility to tumor growth. Notably, Tregs lacking NAC1 not only display elevated lipid metabolism and mitochondrial fitness but also exhibit enhanced tumoral infiltration. Adoptive Treg transfer experiments further underscore the supportive role of NAC1-deficient Tregs in tumor growth. These findings suggest that modulating NAC1 expression in FoxP3⁺ Tregs could serve as a promising approach to augment antitumor immunity. Understanding the intricate interplay between NAC1 and Tregs opens avenues for potential therapeutic strategies targeting the tumor microenvironment (TME).

Metabolic Fitness of NAC1-Deficient Regulatory T Cells in the Tumor Microenvironment Fuels Tumor Growth

Anil Kumar,¹ Jugal Das,¹ Hao-Yun Peng,¹ Liqing Wang,¹ Darby Ballard,¹ Yijie Ren,¹ Xiaofang Xiong,¹ Xingcong Ren,² Jin-Ming Yang,² Paul de Figueiredo,³ and Jianxun Song¹

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Metabolic Fitness of NAC1-Deficient Regulatory T Cells in the Tumor Microenvironment Fuels Tumor Growth

Anil Kumar,1 Jugal Das,1 Hao-Yun Peng,1 Liqing Wang,1 Darby Ballard,1 Yijie Ren,1 Xiaofang Xiong,1 Xingcong Ren,2 Jin-Ming Yang,2 Paul de Figueiredo,3 and Jianxun Song1

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Anil Kumar,¹ Jugal Das,¹ Hao-Yun Peng,¹ Liqing Wang,¹ Darby Ballard,¹ Yijie Ren,¹ Xiaofang Xiong,¹ Xingcong Ren,² Jin-Ming Yang,² Paul de Figueiredo,³ and Jianxun Song¹