Orosomucoid 2 promotes colorectal cancer liver metastasis by suppressing natural killer cell-mediated antitumor immunity by remodeling the serine and one-carbon metabolism pathway

The liver is the most common site of distant metastasis in colorectal cancer (CRC), and liver metastasis (LM) remains the leading cause of CRC-related mortality. The immune microenvironment plays a crucial role in regulating LM progression, but the key molecular drivers involved in its remodeling remain poorly understood. We performed an in vivo CRISPR-Cas9 screen in a murine model of colorectal cancer liver metastasis (CRLM) to identify key regulators of metastatic colonization. In vitro and in vivo functional studies were conducted to evaluate the role and mechanisms of ORM2 in modulating CRLM. We identified orosomucoid 2 (ORM2) as a top candidate whose knockout markedly suppressed CRLM. Clinically, ORM2 expression was significantly upregulated in CRLM tissues and correlated with poor patient prognosis. Genetic ablation of ORM2 significantly reduced LM in vivo. Mechanistically, the pro-metastatic role of ORM2 was dependent on natural killer (NK) cells. Further analyses revealed that ORM2 interacts with activin A receptor type 1 (ACVR1) to activate the Hippo signaling pathway, leading to the suppression of serine and one-carbon metabolism, a key pathway for NK cell cytotoxic function. Our findings uncover a novel immunometabolic mechanism by which tumor-derived ORM2 promotes immune evasion and liver metastasis in CRC. Targeting the ORM2–ACVR1 axis may offer a promising therapeutic strategy for CRLM.