Chuifang Kong, Yanchun Fang, Lili Shen, Zhihua null Shui, Mengjie Lv, Xinyu Zhang, Hu Xu, Xunxia Bao, Pengwei Cao, Wenjing Ding, Tao Yu, Shengming Ruan, Juan Ran, Jiangming Chen, Juling Wang, Dongsheng Hou, Fan Liu, Yanping Wang, Q. li, Daoxiang Zhang
Pancreatic cancer is an aggressive malignancy with poor prognosis and limited treatment options. Recent advances in immunotherapy have shown potential for improving outcomes; however, therapeutic resistance remains a challenge. We demonstrate that HAS2 is significantly upregulated in pancreatic cancer, and is associated with poor prognosis, reduced infiltration of CD4⁺ and CD8⁺ T cells, and shorter survival. Mechanistically, HAS2 stabilizes PD-L1, a key immune checkpoint molecule, by modulating K6- and K63-linked ubiquitination, enhancing PD-L1 stability and suppressing immune responses. Our study further reveals that HAS2 activates the AKT signaling pathway to downregulate March4 expression, a critical E3 ubiquitin ligase that negatively regulates PD-L1 stability, thereby promoting PD-L1 stabilization. In vivo, HAS2 knockout in KPC mice reduces PD-L1 levels, increases March4 expression, enhances T cell infiltration, and delays cancer progression. Reduced collagen deposition in HAS2⁺/⁻ tumors further underscores its role in tumor microenvironment remodeling. Targeting the HAS2-March4-PD-L1 axis through HAS2 inhibition, anti-PD-L1 therapy, or March4 overexpression suppresses tumor growth and improves survival.