Abstract 3454: Charting single-cell metabolism co-evolution during metastasis

Metastasis, the leading cause of cancer death, exhibits a highly heterogeneous and suppressive cancer microenvironment. Here, we sequenced 97 matched samples by using single-cell RNA sequencing and spatial transcriptomics of colorectal cancer liver metastasis. Strikingly, the metastatic microenvironment underwent remarkable spatial reprogramming of immunosuppressive cells such as MRC1+ CCL18+ M2-like macrophages. We further developed scMetabolism, a computational pipeline for quantifying single-cell metabolism, and observed that those macrophages harbored enhanced amino acid metabolic activity. Interestingly, neoadjuvant chemotherapy could block this status and restore the antitumor immune balance in responsive patients, whereas the nonresponsive patients deteriorated into a more suppressive one. In parallel, metastatic cancer cells displayed the metabolic switch from OXPHOS to glycolysis, which is dependent on the metabolic master regulator LY6E. Our work described the metabolism co-evolution of both immune and cancer cells during metastasis and uncovered the black box of how tumors respond to neoadjuvant chemotherapy. Citation Format: Yingcheng Charles Wu. Charting single-cell metabolism co-evolution during metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3454.