Near-Infrared-II Nanoparticles for Vascular Normalization Combined with Immune Checkpoint Blockade via Photodynamic Immunotherapy Inhibit Uveal Melanoma Growth and Metastasis

Photodynamic therapy (PDT) has been widely employed in tumor treatment due to its effectiveness. However, the tumor hypoxic microenvironment which is caused by abnormal vasculature severely limits the efficacy of PDT. Furthermore, the abnormal vasculature has been implicated in the failure of immunotherapy. In this study, a novel nanoparticle denoted as Combo-NP is introduced, composed of a biodegradable NIR II fluorescent pseudo-conjugate polymer featuring disulfide bonds within its main chain, designated as TPA-BD, and the vascular inhibitor Lenvatinib. Combo-NP exhibits dual functionality by not only inducing cytotoxic reactive oxygen species (ROS) to directly eliminate tumor cells but also eliciting immunogenic cell death (ICD). This ICD response, in turn, initiates a robust cascade of immune reactions, thereby augmenting the generation of cytotoxic T lymphocytes (CTLs). In addition, Combo-NP addresses the issue of tumor hypoxia by normalizing the tumor vasculature. This normalization process enhances the efficacy of PDT while concurrently fostering increased CTLs infiltration within the tumor microenvironment. These synergistic effects synergize to potentiate the photodynamic-immunotherapeutic properties of the nanoparticles. Furthermore, when combined with anti-programmed death-ligand 1 (PD-L1), they showcase notable inhibitory effects on tumor metastasis. The findings in this study introduce an innovative nanomedicine strategy aimed at triggering systemic anti-tumor immune responses for the treatment of Uveal melanoma. A nanoparticle (Combo-NP) that contains biodegradable NIR-II-fluorescent pseudo conjugate polymer with disulfide bonds in the main chain (TPA-BD) and a vascular inhibitor Lenvatinib (Len) is designed. Combo-NP not only kill tumors by generating reactive oxygen species (ROS), but also trigger immunogenic cell death (ICD) initiating cascade immune responses leading to the production of cytotoxic T lymphocytes (CTLs). Moreover, Combo-NP alleviate hypoxia by normalizing the tumor vessels, thereby improving the Photodynamic therapy (PDT)efficiency and increasing the infiltration of CTLs. These effects combine to amplify the photodynamic-immunotherapy of the nanoparticles exhibiting promising inhibitory effects on tumor metastasis and inducing an abscopal immune response when combine with anti-programmed death-ligand 1 (PD-L1) immunotherapy.image