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

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.