Polydopamine-based Nanoadjuvants Promote a Positive Feedback Loop for Cancer Immunotherapy via Overcoming Photothermally Boosted T Cell Exhaustion.

Immunogenic cell death, triggered by photothermal therapy or specific chemotherapy, strives to establish a positive feedback loop in cancer immunotherapy. This loop is characterized by the rapid release of antigens and adenosine triphosphate (ATP), ultimately leading to accelerated T cell infiltration. However, this loop is hindered by T cell exhaustion caused by adenosine originating from ATP and glucose deprivation in the immunosuppressive microenvironment. To overcome this challenge, we developed a pH-low insertion peptide-functionalized mesoporous-polydopamine-based nanoadjuvant that incorporates adenosine deaminase and doxorubicin (termed as PPMAD). PPMAD aimed to overcome T cell exhaustion by reducing adenosine consumption and providing an alternative carbon source for CD8⁺ T cell function during glucose starvation. First, PPMAD triggered the burst release of antigens and ATP through photothermal therapy and doxorubicin-induced immunogenic cell death, culminating in the expedited infiltration of T cells. Second, adenosine deaminase depleted adenosine, reducing immunosuppressive agents and generating abundant inosine, which served as an alternative carbon source for CD8⁺ T cells. By implementing this "reducing suppression and broadening sources" strategy, we successfully overcome T cell exhaustion, greatly enhancing the effectiveness of cancer immunotherapy both in vitro and in vivo. Our findings highlighted the positive feedback loop between on-demand photothermal therapy, chemotherapy immunotherapy, and achieving complete tumor response.