Acidic tumor microenvironment–modulated nanoparticle potentiates gastric cancer photoimmunotherapy

• A nanoparticle called FX-11@PEG-Ce6 was designed to enter the cell through protein-mediated endocytosis and effectively target tumor sites in vivo . • FX-11@PEG-Ce6 could kill cells through PDT and promote the maturation of dendritic cells to activate the immune system. • FX-11@PEG-Ce6 could improve the acidic microenvironment to promote the infiltration of CD8 + T cells, increase the levels of TNF-α, IFN-γ and granzyme B in tumors, thereby enhancing the efficacy of α-PD-1 therapy. Immunotherapy, especially anti-PD-1 antibodies (α-PD-1), has revolutionized the landscape of cancer treatment. However, the response rate of α-PD-1 for Gastric Cancer (GC) remains relatively low. The acidic immunosuppressive Tumor Microenvironment (TME) greatly hinders the efficacy of α-PD-1. Thus, therapeutic strategies targeting the acidic TME in GC are highly desired. This study aimed to investigate the effect of FX-11@PEG-Ce6 on the therapeutic efficacy of photoimmunotherapy for gastric cancer. We developed FX-11 encapsulated with PEG-Ce6 nanoparticles (FX-11@PEG-Ce6) for GC photoimmunotherapy. The morphology was observed by transmission electron microscopy. Flow cytometry was performed to detect the maturation level of dendritic cells and the levels of TNF-α, IFN-γ, and granzyme B in CD8 + T cells, and to evaluate the synergistic anti-tumor effects of photoimmunotherapy generated by FX-11@PEG-Ce6 in combination with α-PD-1 in vitro and in vivo . The biological safety of FX-11@PEG-Ce6 was studied by haematoxylin and eosin staining and biochemical analysis of major organs. As a type of nanoplatform, FX-11@PEG-Ce6 demonstrated satisfactory cellular uptake and tumor targeting ability. FX-11@PEG-Ce6 provoked significant immunogenic cell death response. Meanwhile, the results of flow cytometry showed that FX-11@PEG-Ce6 facilitated the maturation of dendritic cells and augmented the secretion of T-cell cytokines. Through the detection of the pH of the cell culture medium, it was revealed that FX-11@PEG-Ce6 could alleviate the acidity of the TME, thereby restoring the function of T cells and enhancing the anti-tumor activity of CD8 + T cells. MFC tumor-bearing mouse models were adopted. In vivo results showed that FX-11@PEG-Ce6 could alleviate the acidic TME and help eradicate tumor cells. FX-11@PEG-Ce6 substantially enhance the efficacy of α-PD-1 and exhibit superior biocompatibility. Our results revealed that the combination of FX-11@PEG-Ce6-based photodynamic therapy and immunotherapy could achieve a synergistic antitumor effect with excellent biosafety, presenting great therapeutic potential for enhanced photoimmunotherapy for GC.