Adaptive Design of Nanovesicles Overcoming Immunotherapeutic Limitations of Chemotherapeutic Drugs through Poliovirus Receptor Blockade.

Abstract

Chemotherapy is currently a widely used treatment for cancer in clinical settings. Some chemotherapeutic drugs such as oxaliplatin (OXA) can cause tumor immunogenic cell death (ICD), activate immunity, and realize chemoimmunotherapy for tumors. However, the low degree of accumulation and immunosuppressive microenvironment in tumors limit the immunotherapeutic efficacy of these drugs. T cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor (PVR) is an inhibitory immune checkpoint pathway involved in mediating natural killer (NK) cell and T cell exhaustion in tumors. TIGIT expression is up-regulated in NK cells and CD8+ T cells during tumor development. Moreover, we first found that tumors upregulated PVR expression after OXA treatment in previous work. Here, we systematically analyzed the effects of OXA on the TIGIT/PVR pathway, further proving the effectiveness of the combination of OXA and TIGIT/PVR blocking combination. We developed engineered TIGIT-expressing cell membrane nanovesicles loaded with OXA (OXA@TIGIT MVs) for synergistic cancer therapy. OXA@TIGIT showed good efficacy in several cancer models, leading to tumor regression, effectively inhibiting tumor growth and prolonging mouse survival. Furthermore, the OXA@TIGIT MVs activate a strong tumor-specific immune response in the body, providing long-term (more than 2 months) protection from tumor reactivation in the B16F10 melanoma rechallenge mouse model.