Despite the potential efficacy of immune checkpoint blockade for effective treatment of cancer, this therapeutic modality is not generally curative, and only a fraction of patients respond. Combination approaches provide strategies to target multiple antitumor immune pathways to induce synergistic antitumor immunity. Here, a multi-combination immunotherapy, including photothermal therapy (PTT), indoleamine-2,3-dioxygenase (IDO) inhibition, and programmed cell death-ligand 1 (PD-L1) blockade, is introduced for inducing synergistic antitumor immunity. We designed a multifunctional IDO inhibitor (IDOi)-loaded reduced graphene oxide (rGO)-based nanosheets (IDOi/rGO nanosheets) with the properties to directly kill tumor cells under laser irradiation and in situ trigger antitumor immune response. In vivo experiments further revealed that the triggered immune response can be synergistically promoted by IDO inhibition and PD-L1 blockade; the responses included the enhancement of tumor-infiltrating lymphocytes, including CD45 + leukocytes, CD4 + T cells, CD8 + T cells, and NK cells; the inhibition of the immune suppression activity of regulator T cells (T regs ); and the production of INF-γ. We also demonstrate that the three combinations of PTT, IDO inhibition, and PD-L1 blockade can effectively inhibit the growth of both irradiated tumors and tumors in distant sites without PTT treatment. This work can be thought of as an important proof of concept to target multiple antitumor immune pathways to induce synergistic antitumor immunity.

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Here, the authors propose a light‐activated reactive oxygen species (ROS)‐responsive nanoplatform that can boost immunogenic cell death (ICD) to release “eat me” signals, and improve CD47‐blocking immunotherapy by tumor‐targeted codelivery of photosensitizer IR820 and anti‐CD47 antibody (αCD47). Human serum albumin and αCD47 are first constructed into a single nanoparticle using ROS‐responsive linkers, which are further conjugated with photosensitizer IR820 via a matrix metalloproteinase‐sensitive peptide as linker and then modified with poly(ethylene glycol) on the surface of the obtained nanoparticles. When exposed to the first wave of near‐infrared (NIR) laser irradiation, the obtained nanoplatform (M‐IR820/αCD47@NP) can generate ROS, which triggers nanoparticles dissociation and thus, facilitates the release of αCD47 and IR820. The second wave of NIR laser irradiation is subsequently used to perform phototherapy and induce ICD of tumor cells. An in vitro cellular study shows that M‐IR820/αCD47@NP can stimulate dendritic cells activation while simultaneously enhancing the phagocytic activity of macrophage against tumor cells. In 4T1 tumor‐bearing mice, M‐IR820/αCD47@NP‐mediated combination of phototherapy and CD47 blockade can effectively induce the synergistic antitumor immune responses to inhibit the growth of tumors and prevent local tumor recurrence. This work offers a promising strategy to improve the CD47‐blocking immunotherapy efficacy using αCD47 nanomedicine.