Chemotherapy triggers immune evasion by fostering LEPR+ Kupffer cell differentiation in liver metastases [CUT&Tag, ATAC-seq]

Conventional chemotherapy achieves clinical efficacy beyond its cytotoxic effects by reactivating immune surveillance. However, whether chemotherapy promotes immune evasion by remodeling the tumor microenvironment (TME) remains largely unexplored. Here, we integrate cross-species single-cell and spatial transcriptomics to explore how chemotherapy reprograms immune cell dynamics and plasticity. Our findings reveal a central role for chemotherapy-educated, liver-resident Kupffer cells (KCs) in promoting immune tolerance and chemoresistance in liver metastases. These reprogrammed KCs, characterized by leptin receptor expression (LEPR+), originate from preexisting KCs and are differentiated via STING-ID1 signaling triggered by cGAMP released from chemotherapy-treated tumor cells. Unlike conventional KCs, LEPR+ KCs infiltrate tumors and engage in MerTK-dependent efferocytosis, which diminishes chemotherapy-induced immunogenic cell death (ICD) and suppresses antitumor immunity. Notably, targeting LEPR+ KCs enhances tumor immunogenicity and strengthens antitumor T-cell responses. Our study demonstrates that therapy-induced KC differentiation fosters immune evasion and suggests combining efferocytosis inhibitors with immunotherapy to overcome chemoresistance.