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

• DOI: 10.1126/sciadv.adn8402
• Publication Date: 2025-03-21T18:22:12Z
• Authors: Xinyu Wang; Yiyi Li; Yan Li; Xiumei Wang; Hongrui Song; Yingzhao Wang; Chunliu Huang; Chengzhou Mao; Lixiang Wang; Cheng Zhong; Di Yu; Zijin Xia; Yongyi Feng; Jingjing Duan; Yujia Liu; Juanjuan Ou; Congzhou Luo; Wenhao Mai; Hai Hong; Weibin Cai; Limin Zheng; Jean-François Trempe; Edward A. Fon; Jing Liao; Wei Yi; Jun Chen

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.