This research reveals that chemotherapy unintentionally triggers immune evasion in liver metastases by reprogramming resident Kupffer cells into a suppressive LEPR+ state. This transition is driven by tumor cells that, when damaged by treatment, release cGAMP to activate STING-ID1 signaling within the liver’s immune environment. Once differentiated, these LEPR+ Kupffer cells infiltrate the tumor and utilize MerTK-dependent efferocytosis to clear away signals that would otherwise activate the immune system. This process effectively hides the cancer from cytotoxic T cells, leading to treatment resistance and eventual disease recurrence. The study suggests that combining chemotherapy with inhibitors that target MerTK or PD-L1 can dismantle this barrier and restore antitumor immunity. Together, these findings identify a specific cellular mechanism behind chemoresistance and provide a roadmap for more effective combination therapies in metastatic liver cancer.

References:

• Wang X, Pan Q, Li Y, et al. Chemotherapy triggers immune evasion by fostering LEPR+ Kupffer cell differentiation in liver metastases[J]. Cancer Cell, 2026.