STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRC

  • Adv Sci (Weinh). 2025 Jan;12(1):e2405083. doi: 10.1002/advs.202405083.
Shiyu Huang  1  2 ,  Xuke Qin  1  2 ,  Shujie Fu  1  2 ,  Juncheng Hu  1  2 ,  Zhengyu Jiang  1  2 ,  Min Hu  3 ,  Banghua Zhang  1  2  4 ,  Jiachen Liu  1  2  5 ,  Yujie Chen  1  2 ,  Minghui Wang  1  2 ,  Xiuheng Liu  1  2 ,  Zhiyuan Chen  1  2 ,  Lei Wang  1  2
Affiliations
  • 1. Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
  • 2. Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
  • 3. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
  • 4. Hubei Key Laboratory of Digestive System Disease, Wuhan, 430060, China.
  • 5. Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China.
PMID: 39527690 DOI: 10.1002/advs.202405083
Abstract

Kidney renal clear cell carcinoma (KIRC) is recognized as an immunogenic tumor, and immunotherapy is incorporated into its treatment landscape for decades. The acquisition of a tumor mesenchymal phenotype through epithelial-to-mesenchymal transition (EMT) is associated with immune evasion and can contribute to immunotherapy resistance. Here, the involvement of STAM Binding Protein Like 1 (STAMBPL1) is reported in the development of mesenchymal and immune evasion phenotypes in KIRC cells. Mechanistically, STAMBPL1 elevated protein abundance and surface accumulation of TAM Receptor AXL through diminishing the TRIM21-mediated K63-linked ubiquitination and subsequent lysosomal degradation of Axl, thereby enhancing the expression of mesenchymal genes while suppressing chemokines CXCL9/10 and HLA/B/C. In addition, STAMBPL1 enhanced PD-L1 transcription via facilitating nuclear translocation of p65, and knockdown (KD) of STAMBPL1 augmented antitumor effects of PD-1 blockade. Furthermore, STAMBPL1 silencing and the tyrosine kinase inhibitor (TKI) sunitinib also exhibited a synergistic effect on the suppression of KIRC. Collectively, targeting the STAMBPL1/TRIM21/Axl axis can decrease mesenchymal phenotype and potentiate anti-tumor efficacy of Cancer therapy.

Keywords
STAM binding protein like 1; immunotherapy resistance; kidney renal clear cell carcinoma; mesenchymal phenotype; ubiquitination.
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