Cancer metastases is still a hurdle for good prognosis and live quality of breast cancer patients. Treatment strategies that can inhibit metastatic cancer while treating primary cancer are needed to improve the therapeutic effect of breast cancer.Methods: In this study, a dual functional drug conjugate comprised of protoporphyrin IX and NLG919, a potent indoleamine-2,3-dioxygenase (IDO) inhibitor, is designed to combine photodynamic therapy and immune checkpoint blockade to achieve both primary tumor and distant metastases inhibition. Liposomal delivery is applied to improve the biocompatibility and tumor accumulation of the drug conjugate (PpIX-NLG@Lipo). A series of in vitro and in vivo experiments were carried out to examine the PDT effect and IDO inhibition activity of PpIX-NLG@Lipo, and subsequently evaluate its anti-tumor capability in the bilateral 4T1 tumor-bearing mice.Results: The in vitro and in vivo experiments demonstrated that PpIX-NLG@Lipo possess strong ability of ROS generation to damage cancer cells directly through PDT. Meanwhile, PpIX-NLG@ Lipo can induce immunogenic cell death to elicit the host immune system. Furthermore, PpIX-NLG@Lipo interferes the activity of IDO, which can amplify PDT-induced immune responses, leading to an increasing amount of CD8+ T lymphocytes infiltrated into tumor site, finally achieve both primary and distant tumor inhibition.Conclusion: This work presents a novel conjugate approach to synergize photodynamic therapy and IDO blockade for enhanced cancer therapy through simultaneously inhibiting both primary and distant metastatic tumor.

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Hypoxia is a typical feature of solid tumors, which highly limits the application of the oxygen-dependent therapy. Also, the dense and hyperbaric tumor tissues impede the penetration of nanoparticles into the deep tumor. Thereby, we designed a novel localized injectable hydrogel combining the photothermal therapy (PTT) and the thermodynamic therapy (TDT), which is based on the generation of free radicals even in the absence of oxygen for hypoxic tumor therapy. In our study, gold nanorods (AuNRs) and 2,2′-Azobis[2-(2-imidazalin-2-yl)propane] dihydrochlaride (AIPH) were incorporated into the hydrogel networks, which were formed by the copolymerization of hydrophobic N-isopropyl acrylamide (NIPAM) and hydrophilic glycidyl methacrylate modified hyaluronic acid (HA-GMA) to fabricate an injectable and near-infrared (NIR) responsive hydrogel. The crosslinked in situ forming hydrogel could not only realize PTT upon the NIR laser irradiation, but also generate free radicals even in hypoxic condition. Meanwhile the shrink of hydrogels upon thermal could accelerate the generation of free radicals to further damage the tumors, achieving the controlled drug release on demand. The designed hydrogel with a sufficient loading capacity, excellent biocompatibility and negligible systemic toxicity could serve as a long-acting implant for NIR-triggered thermo-responsive free radical generation. The in vitro cytotoxicity result and the in vivo antitumor activity illustrated the excellent therapeutic effect of hydrogels even in the absence of oxygen. Therefore, this innovative oxygen-independent platform combining the antitumor effects of PTT and TDT would bring a new insight into hypoxic tumor therapy by the application of alkyl free radical.