MAL2-Driven Lipid Droplets as Trojan Horses: Subverting Immune Surveillance to Promote Colorectal Cancer Liver Metastasis.

Authors

Shipeng Dai, Ziyuan Liu, Junjie Sun, Yanshu He, Hengsong Cao, Hongyu Wang, Yuchen Xie, Tian Huang, Yue Chai, Zhengqing Lu, Pengyu Cheng, Yidong Xia, Yiming Wang, Qingxin Xia, Xuehao Wang, Yongxiang Xia, Li Liu, Xiaopei Hao, Weiwei Tang

Published in

Cancer letters. Pages 218847. Sep 19, 2026. Epub Sep 19, 2026.

Abstract

Colorectal cancer liver metastasis (CRLM) represents a formidable clinical challenge, yet the metabolic mechanisms by which tumor cells dismantle hepatic immune surveillance and remodel the tumor microenvironment (TME) remain elusive. Here, integrating single-cell RNA sequencing (scRNA-seq), transcriptomic analysis, and mass cytometry (CyTOF), we uncover MAL2 as a key regulator of immune-metabolic crosstalk in CRLM. MAL2 is significantly upregulated and specifically enriched in malignant epithelial cells within liver metastatic lesions. Transcriptomic analysis demonstrates that MAL2 activates non-canonical NF-κB (ncNF-κB) signaling, directly driving FASN transcription, enhancing lipid droplet (LD) biogenesis and secretion, and promoting epithelial-mesenchymal transition (EMT). CyTOF-based immune mapping further indicates that these tumor-derived LDs, upon entering the metastatic microenvironment, selectively recruit PLIN2+ neutrophils and induce neutrophil extracellular traps (NETs), which entrap FABP1+ macrophages and forge an immunosuppressive niche that accelerates metastatic outgrowth. Conceptually, these LDs function as "Trojan horses," appearing as innocuous metabolic gifts while harboring hidden MAL2-driven signals. Once inside the liver, they "open the gates" by recruiting and reprogramming myeloid cells, ultimately dismantling immune defenses from within. Our study establishes MAL2-induced LDs as critical mediators of metastatic immune evasion and nominates the MAL2-ncNF-κB-FASN axis as a therapeutic vulnerability in CRLM.

PMID:
42762965
Bibliographic data and abstract were imported from PubMed on 20 Sep 2026.

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