2. Academic Validation
  3. An Epigenetic Nanoagonist Facilitates T Cell Priming, Recruitment, and Reinvigoration in Tumors Resistant to PD-L1 Therapy

An Epigenetic Nanoagonist Facilitates T Cell Priming, Recruitment, and Reinvigoration in Tumors Resistant to PD-L1 Therapy

  • Adv Mater. 2025 Aug 29:e02800. doi: 10.1002/adma.202502800.
Xiejun Zhao 1 2,  Xiangchuan Qin 3,  Ruizhe Wang 4,  Yawen Wang 2 5,  Yinli He 2 5,  Yuchen Wang 6,  Kefeng Li 7,  Peipei Zhang 1,  Chen Yang 1,  Menghan Wang 8,  Yingtong Dong 2,  Xue Shi 2 5,  Jia Ma 1 9,  Jiye Zhang 1,  Xiaojiao Li 2 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P. R. China.
  • 2 BioBank, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P. R. China.
  • 3 Department of Basic Medicine, Xinjiang Medical University and Xinjiang Key Laboratory of Molecular Biology of Endemic Diseases, Urumqi, Xinjiang, 830017, P. R. China.
  • 4 International Research Center for Renewable Energy, State Key Laboratory of Multiphase Flow in Power Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, P. R. China.
  • 5 Shaanxi Engineering Research Center for Biobank and Advanced Medical Research, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P. R. China.
  • 6 Zonglian College, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P. R. China.
  • 7 College of Food Engineering and Nutritional Science, Shaanxi Normal University, 620 West Chang'an Avenue, Xi'an, Shaanxi, 710119, P. R. China.
  • 8 Department of Pharmacy, The first Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P. R. China.
  • 9 Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P. R. China.
PMID: 40883972 DOI: 10.1002/adma.202502800
Abstract

Inefficient priming, poor recruitment, and inadequate reinvigoration of T cells challenges the therapy of PD-L1-resistant tumors. Herein, a pH-responsive charge-reversal nanoplatform integrating coactivator-associated arginine methyltransferase 1 (CARM1) inhibitor (iCARM1) and poliovirus receptor siRNA (siPVR) is developed. Upon tumor penetration, iCARM1 released in tumor cells facilitates T cell priming by epigenetically activating Cyclic GMP-AMP Synthase (cGAS)-stimulator of interferon genes (STING) signaling-mediated dendritic cell maturation. Meanwhile, in T cells, iCARM1 facilitates their recruitment by upregulating CXC-chemokine receptor 3 (CXCR3) expression. The released siPVR silences pvr to reinvigorate T cells. This epigenetic nanoagonist induces a robust immune response, dramatically suppresses tumor growth, metastasis, and relapse, and confers durable protection against secondary tumor challenge. Multiple PD-L1-resistant models demonstrate the broad applicability of this strategy. This study thus represents an innovative approach for facilitating multilevel T cell responses to combat PD-L1-resistant tumors.

Keywords

PD‐L1 resistant tumors; T cell priming; T cell recruitment; T cell reinvigoration; epigenetic nanoagonists.

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