Immunogenic cell death (ICD)-associated immunogenicity can be evoked through reactive oxygen species (ROS) produced via endoplasmic reticulum (ER) stress. In this study, we generate a double ER-targeting strategy to realize photodynamic therapy (PDT) photothermal therapy (PTT) immunotherapy. This nanosystem consists of ER-targeting pardaxin (FAL) peptides modified-, indocyanine green (ICG) conjugated- hollow gold nanospheres (FAL-ICG-HAuNS), together with an oxygen-delivering hemoglobin (Hb) liposome (FAL-Hb lipo), designed to reverse hypoxia. Compared with non-targeting nanosystems, the ER-targeting naosystem induces robust ER stress and calreticulin (CRT) exposure on the cell surface under near-infrared (NIR) light irradiation. CRT, a marker for ICD, acts as an ‘eat me’ signal to stimulate the antigen presenting function of dendritic cells. As a result, a series of immunological responses are activated, including CD8 + T cell proliferation and cytotoxic cytokine secretion. In conclusion, ER-targeting PDT-PTT promoted ICD-associated immunotherapy through direct ROS-based ER stress and exhibited enhanced anti-tumour efficacy.

A convenient and feasible therapeutic strategy for malignant and metastatic tumors was constructed here by combining photothermal ablation (PTA)-based laser immunotherapy with perdurable PD-1 blockade immunotherapy. Hollow gold nanoshells (HAuNS, a photothermal agent) and AUNP12 (an anti PD-1 peptide, APP) were co-encapsulated into poly(lactic- co-glycolic) acid (PLGA) nanoparticles. Unlike monoclonal PD-1/PD-L1 antibodies, PD-1 peptide inhibitor shows lower cost and immunotoxicity but needs frequent administration due to its rapid clearance in vivo. Our data here showed that the formed HAuNS- and APP-loaded PLGA nanoparticles (AA@PN) could maintain release periods of up to 40 days for the peptide, and a single intratumoral injection of AA@PN could replace the frequent administration of free APP. After the administration of AA@PN and irradiation with a near-infrared laser at the tumor site, an excellent killing effect on the primary tumor cells was achieved by the PTA. The nanoparticles also played a vaccine-like role under the adjuvant of cytosine-phospho-guanine (CpG) oligodeoxynucleotide and generated a localized antitumor-immune response. Furthermore, sustained APP release with laser-dependent transient triggering could induce the blockage of PD-1/PD-L1 pathway to activate T cells, thus subsequently generating a systemic immune response. Our data demonstrated that the PTA combined with perdurable PD-1 blocking could efficiently eradicate the primary tumors and inhibit the growth of metastatic tumors as well as their formation. The present study provides a promising therapeutic strategy for the treatment of advanced cancer with metastasis and presents a valuable reference for obtaining better outcomes in clinical cancer immunotherapy.

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Both photothermal therapy (PTT) and photodynamic therapy (PDT) are phototherapeutic approaches, which have been widely investigated for cancer therapy mediated by an external light source. Here, a nanosystem presenting the synchronous PTT and PDT effect realized through one-step near-infrared (NIR) light irradiation is reported. This system was fabricated by conjugating indocyanine green (ICG) on hollow gold nanospheres (HAuNS) using branched-polyethylenimine (PEI, MW = 10 kDa) as optimal linker, which provided a high ICG payload as well as a covering layer with suitable thickness on HAuNS to maintain ICG fluorescence and reactive oxygen species (ROS) productivity. The resulting system (ICG-PEI-HAuNS) had the molar ratio of ICG:PEI:Au = 3:0.33:5. Compared with free ICG, ICG-PEI-HAuNS exhibited dramatically enhanced stability of ICG molecules and greater intratumoral accumulation. The conjugation of ICG caused significantly higher plasmon absorption of ICG-PEI-HAuNS in the NIR region compared with HAuNS alone, inducing remarkably enhanced photothermal conversion efficiency and synchronous photodynamic effect under NIR light irradiation. Interestingly, compared with PTT or PDT alone, synchronous PTT and PDT produced by ICG-PEI-HAuNS upon NIR light irradiation induced significantly stronger antitumor and metastasis inhibition effects both in vitro and in vivo, which might be a promising strategy for cancer treatment.

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