Lactylated Apolipoprotein C‐II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis

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-APOC2^K70-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.