Optimization of Cancer Immunotherapy Through Synergistic Enhancement of Immunogenic Cell Death by Multifunctional Nanobioreactors Combined with Immune Checkpoint Inhibitors

Immune checkpoint blocking therapy (ICB) has shown great promise in cancer treatment. However, only a minority of patients benefit from ICB due to an immunosuppressive tumor microenvironment. To address this problem, we adopted a strategy of multimodal synergies to enhance the immunogenic cell death (ICD). In this study, a multifunctional nanodelivery system, hyaluronic acid (HA) nanomicelles (HPCC), was synthesized. HPCC was constructed by self-assembly of hyaluronic acid-cinnamaldehyde Schiff base (HA-CA) and copper–carbon dots modified with pyromagnesia chlorophyllin acid (CuCDs-PPa). HPCC showed sensitive photothermal imaging in image-guided therapy and showed a good synergistic effect in killing tumor cells in combination with chemodynamic therapy-phototherapy (chemo-phototherapy). HPCC releases CuCDs-PPa in response to pH stimulation, CuCDs-PPa activates PDT and PTT under dual light excitation (660 nm laser and 750 nm laser), Cu 2+ Fenton-like reaction activates CDT, and Cu 2+ consumes glutathione to amplify reactive oxygen species. Chemo-phototherapy induced immunogenic cell death (ICD) and T cell activation sensitized immune checkpoint block (αPD-L1) responses, thereby triggering systemic antitumor immunity. In animal experiments with double tumor models, it was finally observed that the primary tumor was highly inhibited, and the distal tumor growth was inhibited, which may be the result of the combined action of CDT, PTT, PDT and αPD-L1. In this study, an innovative image-mediated combination therapy strategy involving multifunctional nanoagents is proposed that may provide avenues for the clinical treatment of cancer.