2. Academic Validation
  3. STAM2-mediated fine-tuning of PD-L1 secretion via small extracellular vesicles in oral squamous cell carcinoma

STAM2-mediated fine-tuning of PD-L1 secretion via small extracellular vesicles in oral squamous cell carcinoma

  • Int J Biol Macromol. 2025 Jun 18;319(Pt 2):145350. doi: 10.1016/j.ijbiomac.2025.145350.
Xiao-Le Wang 1,  Hou-Fu Xia 2,  Zhuo-Kun Chen 3,  Kui-Ming Wang 3,  Wei Zhang 4,  Gang Chen 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
  • 2 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China. Electronic address: xiahoufuw@whu.edu.cn.
  • 3 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
  • 4 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China. Electronic address: wzhang88@whu.edu.cn.
  • 5 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, China. Electronic address: geraldchan@whu.edu.cn.
PMID: 40541896 DOI: 10.1016/j.ijbiomac.2025.145350
Abstract

The secretion of programmed death ligand 1 (PD-L1) via small extracellular vesicles (sEVs) endows this immune checkpoint protein with diverse and systemic roles. This intercellular communication mediated by sEV PD-L1 not only fosters a pro-tumorigenic niche but also induces systematic immunosuppression. Revealing the intricate mechanisms underlying sEV PD-L1 secretion is essential for understanding tumor pathology and developing targeted therapies. Here, we demonstrated the specialization and collaboration among members of the endosomal sorting complex required for transport-0 (ESCRT-0) family in regulating sEV PD-L1 secretion in oral squamous cell carcinoma (OSCC). Mechanistically, STAM2, not STAM1, directly binds cell surface PD-L1, followed by recruiting HRS to initiate the biogenesis of PD-L1+ sEVs. Specifically, STAM2 binds the functional domains of PD-L1 and HRS through the VHS and ITAM domains respectively, acting as a molecular bridge between PD-L1 and HRS. Therefore, our study delineated the sequential participation of different ESCRT-0 members during sEV PD-L1 secretion and highlighted the pivotal role of STAM2 in orchestrating this process, providing important insights into diseases with aberrant PD-L1 secretion, such as OSCC.

Keywords

HRS; PD-L1; STAM2; Small extracellular vesicle.

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