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

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.