MARCO macrophages drive immunosuppressive remodeling and metastasis in chemotherapy-associated steatohepatitis.

[BACKGROUND & AIMS] Chemotherapy-associated steatohepatitis (CASH) is a common side effect of treatment in patients with colorectal liver metastases (CRLM) that may affect patient outcomes. However, the underlying mechanisms of CASH remain poorly understood.

[METHODS] CD45 cells were isolated from liver tissues of 10 patients with CRLM who developed CASH following irinotecan-based chemotherapy. These cells were subjected to integrated single-cell transcriptomic and immune profiling analyses. Twenty-four pairs of human CASH samples, a clinical cohort, and irinotecan-induced CASH mouse models were used to confirm the mechanism.

[RESULTS] CASH is associated with high recurrence rates in patients with CRLM. Compared to patients without CASH, those with CASH exhibit an immune microenvironment enriched in MARCO macrophages with immunosuppressive features. The infiltration level of these macrophages correlates with recurrence rates in patients with colorectal cancer. This environment is further defined by the presence of exhausted CD8 TOX T cells and highly stressed, activated DNAJB1 NK cells. Using an irinotecan-induced CASH mouse model, we demonstrated that MARCO macrophages emerge specifically during the steatohepatitis phase, not the acute liver injury stage, and actively promote tumor growth and liver metastasis. Critically, genetic ablation of MARCO significantly inhibited CLRM and reduced the infiltration of CD8 TOX T cells.

[CONCLUSIONS] This study uncovers a distinct immunoregulatory network in CASH, highlighting potential avenues to mitigate chemotherapy-associated hepatic injury and to develop novel immunotherapeutic strategies for patients with liver metastases.

[IMPACT AND IMPLICATIONS] Chemotherapy-associated steatohepatitis (CASH) is a common side effect of treatment in patients with colorectal liver metastases (CRLM) that may affect patient outcomes. However, the mechanisms remain poorly understood. Herein, we identify a distinct immune microenvironment in the livers of patients with CASH that is centered on MARCO macrophages and accompanied by increased infiltration of CD8 TOX T cells and DNAJB1 NK cells. This regulatory network participates in disrupting liver antitumor immune responses and is associated with high recurrence rates in patients with CRLM. Our findings provide potential avenues for mitigating chemotherapy side effects and developing novel immunotherapeutic strategies for patients with liver metastases.