Napabucasin transforms liver microenvironment and boosts immunotherapy efficacy by converting potential metastases into “hot” tumors

Abstract Liver metastases often respond poorly to immunotherapy because of a “cold” tumor microenvironment characterized by limited lymphocyte infiltration. Napabucasin, a small‐molecule naphthoquinone, has been suggested to modulate the tumor microenvironment. This preclinical study investigates whether Napabucasin enhances immunotherapy efficacy and prevents liver metastasis. Pretreatment with Napabucasin before tumor inoculation significantly reduces liver metastases in mice and increases immune cell infiltration within metastatic lesions. Mechanistically, Napabucasin induces secretion of the chemokine C–C motif ligand 21 (CCL21) from hepatocytes through activation of the transcription factor c‐Fos, leading to the recruitment of lymphocytes into the liver. This immunomodulatory effect is cancer cell–independent and liver‐specific, with no effect on splenic, lung, or subcutaneous tumors and no CCL21 upregulation in other organs. The recruited T lymphocytes co‐express immune activators and immune checkpoint molecules, indicating a phenotype suitable for reactivation by immune checkpoint inhibitors. Clinical transcriptomic data further show that a Napabucasin‐associated gene signature correlates with improved immunotherapy responses. Consistently, Napabucasin pretreatment sensitizes liver metastases to anti–PD‐1/programmed death‐ligand 1 (PD‐L1) therapy in mice. Overall, these findings demonstrate that early administration of Napabucasin reprograms the hepatic microenvironment, converts potential liver metastases into immunologically “hot” tumors, and enhances the efficacy of immune checkpoint blockade.