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

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.