31P - Napabucasin transforms liver microenvironment and boosts immunotherapy efficacy by converting potential metastases into “hot” tumors

Background

Liver metastases are often considered as "cold" tumors, characterized by a lack of T-cell infiltration. This makes them less responsive to immunotherapies. Napabucasin, a small molecule inhibitor, has shown clinical safety but the specific patient population and therapeutic combination strategies require further optimization. We hypothesize that Napabucasin's microenvironment-modulating properties could enhance immunotherapy efficacy or even prevent liver metastasis.

Methods

Napabucasin was administered to mice via gavage for one week before the induction of a liver metastasis model through spleen injection of mouse colon cancer MC38 cells. This allowed us to study the drug's impact on the microenvironment independently of tumor cells. Then, mice were treated with the anti-PD-1/PD-L1 inhibitor BMS-1. Concurrently, in vitro experiments were performed to explore the mechanisms.

Results

Napabucasin pretreatment significantly reduced the liver metastatic burden. In cases where metastases developed, pretreated mice showed enhanced immune cell infiltration within the lesions. Before cancer cells arrived, Napabucasin pretreatment had already increased lymphocyte infiltration in liver and elevated CCL21 expression in hepatocytes. Notably, this effect was specific to the liver, with no observed impact on CCL21 mRNA expression in other organs. Both in vivo and in vitro data supported that Napabucasin induced CCL21 secretion from hepatocytes via the c-Fos pathway, leading to the attraction of T lymphocytes and other immune cells. Clinical data analysis showed that high CCL21 expression is associated with positive immunotherapy responses in various cancers, including melanoma and esophagus adenocarcinoma. Finally, Napabucasin pretreatment is confirmed to sensitize the liver tumor to BMS-1.

Conclusions

Napabucasin can improve the immunological microenvironment of the liver in advance and make the subsequent potential metastases to be "hot" tumors. The early application of Napabucasin is not only beneficial for the prevention of liver metastasis but also enhances the therapeutic efficacy of immunotherapy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

The National Natural Science Foundation of China (82373009).

Disclosure

All authors have declared no conflicts of interest.