AMPK-dependent Parkin activation suppresses macrophage antigen presentation to promote tumor progression

The constrained cross-talk between myeloid cells and T cells in the tumor immune microenvironment (TIME) restricts cancer immunotherapy efficacy, whereas the underlying mechanism remains elusive. Parkin, an E3 ubiquitin ligase renowned for mitochondrial quality control, has emerged as a regulator of immune response. Here, we show that both systemic and macrophage-specific ablations of Parkin in mice lead to attenuated tumor progression and prolonged mouse survival. By single-cell RNA-seq and flow cytometry, we demonstrate that Parkin deficiency reshapes the TIME through activating both innate and adaptive immunities to control tumor progression and recurrence. Mechanistically, Parkin activation by AMP-activated protein kinase rather than PTEN-induced kinase 1 mediated major histocompatibility complex I down-regulation on macrophages via Autophagy related 5-dependent autophagy. Furthermore, Parkin deletion synergizes with immune checkpoint blockade treatment and Park2^-/- signature aids in predicting the prognosis of patients with solid tumor. Our findings uncover Parkin's involvement in suppressing macrophage antigen presentation for coordinating the cross-talk between macrophages and T cells.