Targeting HAS2 to enhance anti-tumor immunity in pancreatic cancer via PD-L1 regulation

  • Commun Biol. 2026 Apr 8;9(1):764. doi: 10.1038/s42003-026-10009-1.
Chuifang Kong  #  1 ,  Yanchun Fang  #  2 ,  Lili Shen  3 ,  Zhihua Shui  1 ,  Mengjie Lv  1 ,  Xinyu Zhang  1 ,  Hanmeng Xu  1 ,  Xunxia Bao  1 ,  Pengwei Cao  1 ,  Wenjing Ding  1 ,  Tengfei Yu  1 ,  Shengming Ruan  1 ,  Juan Ran  1 ,  Jiangming Chen  4 ,  Juling Wang  1 ,  Dongsheng Hou  5 ,  Fubao Liu  4 ,  Yanping Wang  6 ,  Qiong Li  7 ,  Daoxiang Zhang  8
Affiliations
  • 1. School of Life Sciences, Anhui medical University, Hefei, China.
  • 2. Department of Pathology, Nantong Haimen District People's Hospital, Nantong City, China.
  • 3. The Second People's Hospital of Chizhou, Chizhou, China.
  • 4. Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 5. Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
  • 6. Department of Pathology, Nantong Haimen District People's Hospital, Nantong City, China. [email protected].
  • 7. Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. [email protected].
  • 8. School of Life Sciences, Anhui medical University, Hefei, China. [email protected].
  • # Contributed equally.
PMID: 41951812 DOI: 10.1038/s42003-026-10009-1
Abstract

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.

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