British journal of cancer · 2026
Lipid metabolic reprogramming of macrophage by host APOBEC3 deficiency enhances anti-tumor immunity.
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Yang Yuqi, Li Fanglin, Lei Mozi, Liu Yi, Lu Jiangling, Chen Chen, Cui Danyang, Long Yiru, Yu Xiaolu, Sun Jianhua, Chen Jing, Liu Nan, Wang Bingshun, Gong Likun
Аннотация
BACKGROUND: Tumour-associated macrophages are an indispensable part of the tumour immune microenvironment, exhibiting phenotypic and functional plasticity that enables them to play an important role in modulating the immune response. A large number of RNA editing events have been identified during macrophage functional remodelling. APOBEC3 is a well-known family of base-editing enzymes, but whether and how it regulates macrophage function is unclear.
METHODS: In this study, we mainly used genetically engineered mice to demonstrate how host APOBEC3 deficiency affects tumour progression.
RESULTS: We found that the polarisation state of macrophages in the tumour microenvironment was altered by host APOBEC3 deficiency and that knockout of host APOBEC3 significantly inhibited tumour growth and metastasis in a macrophage-dependent manner. Moreover, APOBEC3 deficiency remodelled macrophage function, improved their polarisation state, and enhanced their phagocytic capacity. Mechanistically, APOBEC3 knockout attenuated lipid uptake by macrophages in a PPARγ pathway-dependent way, leading to an increase of M1/M2 ratio in macrophages.
CONCLUSIONS: These findings reveal that APOBEC3 deficiency drives lipid metabolism reprogramming in macrophages and remodels their functions, thereby inducing a strong anti-tumour immune response, providing a proof-of-concept and new insights for the development of the APOBEC3 family for novel tumour therapies. Host APOBEC3 deficiency regulates macrophage function through lipid metabolic remodelling, ultimately leading to tumour suppression (Created with BioRender.com).
METHODS: In this study, we mainly used genetically engineered mice to demonstrate how host APOBEC3 deficiency affects tumour progression.
RESULTS: We found that the polarisation state of macrophages in the tumour microenvironment was altered by host APOBEC3 deficiency and that knockout of host APOBEC3 significantly inhibited tumour growth and metastasis in a macrophage-dependent manner. Moreover, APOBEC3 deficiency remodelled macrophage function, improved their polarisation state, and enhanced their phagocytic capacity. Mechanistically, APOBEC3 knockout attenuated lipid uptake by macrophages in a PPARγ pathway-dependent way, leading to an increase of M1/M2 ratio in macrophages.
CONCLUSIONS: These findings reveal that APOBEC3 deficiency drives lipid metabolism reprogramming in macrophages and remodels their functions, thereby inducing a strong anti-tumour immune response, providing a proof-of-concept and new insights for the development of the APOBEC3 family for novel tumour therapies. Host APOBEC3 deficiency regulates macrophage function through lipid metabolic remodelling, ultimately leading to tumour suppression (Created with BioRender.com).