Single-cell and spatial transcriptomic landscapes reveal PIGT as a pivotal regulator of immunometabolic remodeling in colorectal cancer liver metastasis

Abstract

Colorectal cancer liver metastasis (CRLM) represents the leading cause of mortality in colorectal cancer (CRC). However, the molecular mechanisms enabling metastatic adaptation within the hepatic microenvironment remain unclear. We integrated single-cell RNA sequencing, spatial transcriptomics, and bulk transcriptomic data from CRC patients to characterize the immunometabolic landscape of CRLM. Machine learning models were used to identify key regulators, and functional assays were conducted to validate their biological roles. Nine major cell populations were delineated within CRLM, revealing enrichment of myeloid-derived suppressor cells and depletion of fibroblasts in metastatic lesions. Malignant cells displayed pronounced chromosomal instability and metabolic reprogramming. Among candidate regulators, PIGT emerged as a pivotal node linking metabolic adaptation and immune suppression. PIGT expression increased progressively from primary to metastatic states and was associated with immunosuppressive MIF, SPP1, and TGFβ signaling. Spatial transcriptomics demonstrated colocalization of PIGT-high tumor cells with ITGAM⁺ and CD163⁺ macrophages. Functionally, PIGT knockdown significantly suppressed cell invasion, migration, proliferation, and wound healing in vitro. Conversely, transcriptomic and qPCR analyses showed that PIGT-low tumors exhibited higher expression of inflammatory genes enriched in the IL-17 and TNF signaling pathways. Our integrative multi-omics and experimental analyses identify PIGT as a central regulator bridging tumor metabolism and immune modulation in CRLM. These findings highlight PIGT as a promising prognostic biomarker and potential therapeutic target for metastatic colorectal cancer.