Targeting AKR1B1 reprograms tumor-associated macrophages to enhance antitumor immunity.

BACKGROUND: Tumor-associated macrophages (TAMs) are key drivers of the immunosuppressive tumor microenvironment (TME), thereby limiting the efficacy of immune checkpoint inhibitors (ICIs). However, the underlying mechanisms remain unclear. METHODS: Both genetic (Akr1b3 knockout) and pharmacologic (epalrestat) approaches were employed to examine the impact of Aldo-keto reductase family 1 member B1 (AKR1B1) inhibition on TAMs and T-cell function in vitro and in vivo. Mechanistic insights were obtained through RNA sequencing, flow cytometry, immunofluorescence staining, and co-culture assays. To assess therapeutic relevance, 4T1 breast cancer and LLC lung carcinoma mouse models were used to evaluate the effects of epalrestat on tumor growth, immune infiltration, and T-cell responses. Clinical relevance was validated in patient cohorts with triple-negative breast cancer (TNBC) and lung adenocarcinoma (LUAD). RESULTS: AKR1B1 is highly expressed in TAMs and correlates with CD8(+) T-cell dysfunction. Targeting AKR1B1 enhances antitumor immunity by reprogramming TAMs. Mechanistically, AKR1B1 modulates macrophage metabolism via the glutathione/reactive oxygen species axis, suppressing nuclear factor κB activation and downregulating C-C motif chemokine ligand 5 (CCL5) production, thereby inducing CD8(+) T-cell dysfunction and establishing an immunosuppressive TME. Inhibition of AKR1B1, either by gene knockout or selective pharmacologic blockade, reprograms TAMs toward an immunostimulatory phenotype, increases CCL5-CCR5 (C-C motif chemokine receptor 5) signaling, restores CD8(+)T cell effector function, and strengthens antitumor immunity. Clinically, high AKR1B1 expression is associated with poor prognosis and immune suppression in TNBC and LUAD. Notably, targeting AKR1B1 improves responses to ICIs in both breast and lung cancer models. CONCLUSIONS: AKR1B1 as a critical regulator of TAM-mediated immunosuppression and highlight its therapeutic potential to enhance the efficacy of ICIs.