%0 Journal Article
%T Lactylated Apolipoprotein C-II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis.
%A Chen J
%A Zhao D
%A Wang Y
%A Liu M
%A Zhang Y
%A Feng T
%A Xiao C
%A Song H
%A Miao R
%A Xu L
%A Chen H
%A Qiu X
%A Xu Y
%A Xu J
%A Cui Z
%A Wang W
%A Quan Y
%A Zhu Y
%A Huang C
%A Zheng SG
%A Zhao JY
%A Zhu T
%A Sun L
%A Fan G
%J Adv Sci (Weinh)
%V 0
%N 0
%D 2024 Jul 9
%M 38981044
%F 17.521
%R 10.1002/advs.202406333
%X Mortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non-histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi-omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl-APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti-APOC2K70-lac antibody that sensitized anti-PD-1 therapy in vivo is developed. This findings highlight the potential of anti lactyl-APOC2-K70 approach as a new combination therapy for sensitizing immunotherapeutic responses.