Research On Immunogenic Cell Death Of Tumor Cells Induced By Nano-enabled Photodynamic Therapy

Cancer becomes the the leading challenge in the current clinical cancer treatment with high recurrence rate,distant metastasis,and a poor prognosis.Currently used gold-standard cancer treatment approaches,surgery,chemotherapy and radiotherapy have been widely employed to destroy the primary tumors,but all fail to effectively inhibit the distant metastasis.Thus,an ideal cancer therapeutic strategy with high efficiency and low toxicities would not only destroy the primary tumors,but above all stimulate the immune system to recognize and eliminate residual tumor cel s and prevent metastasis.In this study,human serum albumin was hybridized with hemoglobin by intermolecular disulfide bonds to develop a Ce6-loaded hybrid protein oxygen nanocarrier(C@HPOC)for oxygen self-sufficient photodynamic therapy(PDT).Based on a 4T1 mTNBC murine model,in addition to evaluating the efficacy of C@HPOC-mediated PDT,we also explored its anti-tumor mechanism in vitro and in vivo.In vitro,low-dose(1.0?g/mL of Ce6)C@HPOC not only produced massive reactive oxygen species under laser irradiation leading to high cell cytotoxicity,but also effectively induced immunogenic cell death with enhanced immunogenic signaling molecules release to promote the maturation of dendritic cells.Furthermore,the results in vivo showed that benefited from the tumor-targeted co-delivery of oxygen and photosensitizer,C@HPOC relieved tumor hypoxia and then significantly elevated the generation of singlet oxygen in tumors under laser irradiation.More importantly,C@HPOC-mediated PDT enhanced the calreticulin exposure in tumors to promote the maturation of dendritic cells,and then increased the proportion of activated CD8~+T,CD4~+T,and NK cells both in tumors and tumor draining lymph nodes.The therapeutic effect on mice demonstrated that C@HPOC-mediated PDT could destroy the primary tumors and effectively suppress the distant tumors and lung metastasis by stimulating systemic anti-tumor immune responses.This study provides a new paradigm of oxygen-augmented immunogenic PDT for advanced or metastatic cancers treatment.