2. Academic Validation
  3. Synergistic blockade of SHP-2 and A2AR signal pathways with targeted nanoparticles restores anti-tumor immunity of CD8+ T cells

Synergistic blockade of SHP-2 and A2AR signal pathways with targeted nanoparticles restores anti-tumor immunity of CD8+ T cells

  • J Control Release. 2025 Aug 10:384:113889. doi: 10.1016/j.jconrel.2025.113889.
Mingshui Chen 1,  Lingyu Zhang 2,  Wansong Lin 3,  Zhifeng Zhou 3,  Yang Wang 3,  Ling Wang 3,  Hexi Gu 4,  Jieyu Li 5,  Zhi Ping Xu 6
Affiliations

Affiliations

  • 1 Laboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian 350014, China. Electronic address: 838195033@qq.com.
  • 2 Laboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian 350014, China.
  • 3 Laboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian 350014, China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China.
  • 4 The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China.
  • 5 Laboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian 350014, China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, China. Electronic address: ljy2018@fjzlhospital.com.
  • 6 Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia; Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen 518107, China. Electronic address: gordonxu@uq.edu.au.
PMID: 40425093 DOI: 10.1016/j.jconrel.2025.113889
Abstract

Anti-PD-1/PD-L1-based immune checkpoint blockade targeting T cell immunoregulatory proteins has revolutionized Cancer treatment. However, only a limited number of patients benefit from this therapy due to the therapeutic resistance and inhibitory pathways Other than PD-1 in T cells. Here, we report a new strategy to restore and enhance effector T cell functions through nanoparticle-induced synergistic target of immune checkpoints. SHP099, an allosteric inhibitor for Src-homology domain-containing protein tyrosine phosphatase-2 (SHP2), and CPI-444, a selected inhibitor for adenosine A2AR receptor, were co-encapsulated in a T cell-targeting nanoparticle (SCNP/αCD8). SCNP/αCD8 nanoparticles showed preferable internalization by CD8+ T cells and efficiently blocked SHP2 and A2AR signaling pathways. The simultaneous blockade thus enhanced proliferation, cytokine secretion, cytotoxic function and antitumor activity of CD8+ T cells and significantly inhibited tumor growth in the mouse model. The enhanced anti-tumor immunity in vivo is also ascribed to improved infiltration of effector CD8+ T cells in tumor tissues. These findings suggest that concurrent blockade of A2AR and SHP2 immune checkpoint signaling pathways with small molecule inhibitors offers a promising alternative strategy to enhance T cell functions for enhanced Cancer Immunotherapy.

Keywords

Cancer immunotherapy; Dual blockade of immune checkpoints; Reactivation of T cell function; T cell-targeted nanoparticles.

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