Engineered NIR-Responsive Exosomes for Synergistic Photoimmunotherapy of Hepatocellular Carcinoma

T-cell immunotherapy holds tremendous promise for treating various types of cancer by boosting the infiltration and activity of T cells within tumor tissues. However, efficient recruitment of peripheral T cells to the tumor microenvironment (TME) remains a major clinical challenge. To address this limitation, here, we report an exosomal (EXO) immunotherapy for remodeling the immunosuppressive TME of hepatocellular carcinoma (HCC) into an immunosupportive state in a remotely controllable manner, for which the HCC-secreted exosomes are engineered with CXCL9 chemokine and cypate photothermal transducers (cypate@EXO-CXCL9). The engineered exosomes could efficiently home to the HCC site through homotypic targeting. Upon exposure to near-infrared light, the cypate-mediated photothermal effect readily induces immunogenic death of tumor cells while simultaneously disrupting the exosomes to release CXCL9. The released CXCL9 effectively attracts T cells to the tumor site and is subsequently activated by the HCC-derived antigens and damage associated molecular patterns to mount robust antitumor immunity. This study provides a facile strategy for the remodeling of the immunosuppressive HCC microenvironment, offering an approach for improving immunotherapeutic efficacy of solid tumors in the clinic.