Lactylated apolipoprotein C-II (APOC2) promotes extracellular lipolysis, leading to immunotherapy resistance in non-small-cell lung cancer (NSCLC). This study reveals that lactate induces lactyl-APOC2-K70, which stabilizes APOC2 and increases free fatty acid (FFA) release, promoting regulatory T cell (Treg) accumulation and tumor metastasis. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing the protein and facilitating FFA release. This process is mediated by P300, which promotes APOC2-K70 lactylation, while HDAC3 delactylates APOC2. The anti-APOC2-K70-lac antibody sensitizes anti-PD-1 therapy by inhibiting lactyl-APOC2, reducing Treg accumulation and enhancing immunotherapy efficacy. Lactyl-APOC2-K70 is associated with tumor progression and immunotherapy resistance in NSCLC samples, with higher levels correlating with poor prognosis. The findings highlight the potential of targeting lactyl-APOC2-K70 as a novel therapeutic strategy for NSCLC.Lactylated apolipoprotein C-II (APOC2) promotes extracellular lipolysis, leading to immunotherapy resistance in non-small-cell lung cancer (NSCLC). This study reveals that lactate induces lactyl-APOC2-K70, which stabilizes APOC2 and increases free fatty acid (FFA) release, promoting regulatory T cell (Treg) accumulation and tumor metastasis. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing the protein and facilitating FFA release. This process is mediated by P300, which promotes APOC2-K70 lactylation, while HDAC3 delactylates APOC2. The anti-APOC2-K70-lac antibody sensitizes anti-PD-1 therapy by inhibiting lactyl-APOC2, reducing Treg accumulation and enhancing immunotherapy efficacy. Lactyl-APOC2-K70 is associated with tumor progression and immunotherapy resistance in NSCLC samples, with higher levels correlating with poor prognosis. The findings highlight the potential of targeting lactyl-APOC2-K70 as a novel therapeutic strategy for NSCLC.