Chemotherapy triggers immune evasion by fostering LEPR+ Kupffer cell differentiation in liver metastases.

Conventional chemotherapy achieves clinical efficacy not only through its cytotoxic effects but also by reactivating immune surveillance. However, whether chemotherapy can inversely suppress antitumor immunity remains largely unexplored. Here, we integrate cross-species single-cell and spatial transcriptomics to investigate how chemotherapy programs immune cell plasticity. Our findings reveal that chemotherapy-educated liver-resident Kupffer cells (KCs) promote immune evasion and chemoresistance in liver metastases. These reprogrammed KCs, characterized by leptin receptor expression (LEPR+), originate from preexisting KCs and differentiate via STING (Stimulator of interferon genes)-ID1 signaling, driven by paracrine cGAMP (cyclic GMP-AMP) released from chemotherapy-treated tumor cells. Unlike conventional KCs at the tumor periphery, LEPR+ KCs infiltrate tumors and suppress antitumor immunity through MerTK-dependent efferocytosis that eliminates chemotherapy-induced immunogenic cell death (ICD) signals. Targeting LEPR+ KCs enhances tumor immunogenicity and promotes antitumor T cell responses. Together, our study highlights the potential of combining efferocytosis inhibitors with immunotherapy to overcome chemoresistance.