Abstract Colorectal cancer liver metastasis (CRLM) remains a major challenge in clinical treatment, with its recurrence and poor prognosis closely linked to tumor microenvironment (TME) reprogramming and immune cell dysfunction. As core immunoregulatory cells in the CRLM microenvironment, tumor-associated macrophages (TAMs) undergo significant metabolic reprogramming during disease progression; however, the mechanism by which metabolic reprogramming regulates TAM phenotype and promotes tumor metastasis has not been fully elucidated.A multi-omics strategy integrated single-cell RNA sequencing (scRNA-seq) and ICGC-ARGO/GEO transcriptomic data to analyze metabolic dynamics in CRLM lesions. TAMs were stratified into high (HCTAM), medium, and low (LCTAM) subgroups by cholesterol metabolic activity. Spatial transcriptomics (ST) verified spatial gene expression and metabolic activity, and in vitro functional experiments validated gene functions and regulatory relationships.Cholesterol metabolic pathways were abnormally upregulated in CRLM lesions, with TAMs exhibiting the highest cholesterol metabolic activity among immune and stromal cells. HCTAMs had significantly elevated M2 polarization scores, localized to late-stage macrophage differentiation, and co-expressed multiple M2 markers. Five machine learning algorithms identified lipoprotein lipase (LPL) as significantly overexpressed in HCTAMs, with high LPL expression independently associated with advanced CRC stages and poor overall survival. Mechanistically, lactate dehydrogenase A (LDHA) was significantly upregulated in HCTAMs, and TAM cholesterol metabolic was activity positively correlated with TME acidosis scores. ST confirmed LPL enrichment in acidotic regions, and multiplex immunofluorescence showed LPL colocalization with pan-lactylation. Lactate-induced lactylation modification regulated the expression of LPL . Transcriptomic analysis revealed significant EMT pathway enrichment in CRC cells of high-LPL group. In vitro experiments confirmed LPL colocalization with M2 TAM marker CD163; TAM LPL knockdown reduced cholesterol levels and downregulated M2 polarization markers. Co-culture experiments showed LPL-knockdown TAMs inhibited the invasion and migration of CRC cells and downregulated EMT-related marker expression.In conclusion, this study confirms that the acidic microenvironment in CRLM lesions drives LPL overexpression in TAMs through lactate-dependent lactylation modification. This effect maintains high cholesterol metabolic activity in TAMs and promotes their M2 polarization, further enhancing CRC cell EMT progression and invasiveness, ultimately exacerbating CRLM development. Citation Format: Yifan Zheng, Zhengyu Wei, Zhengran Zhou, Peishan Hu, . The acidic tumor microenvironment facilitates colorectal cancer liver metastasis through LPL lactylation-mediated reprogramming of macrophage cholesterol metabolism abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4137.
Zheng et al. (Fri,) studied this question.