The blocking of the immune checkpoint pathway with antibodies, especially targeting to programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway, was currently a widely used treatment strategy in clinical practice. However, the shortcomings of PD-L1 antibodies were constantly exposed with the deepening of its research and their therapeutic effect was limited by the translocation and redistribution of intracellular PD-L1. Herein, we proposed to improve immune checkpoint blockade therapy by using liposomes-coated CaO₂ (CaO₂@Lipo) nanoparticles to inhibit the de novo biosynthesis of PD-L1. CaO₂@Lipo would produce oxygen and reduce hypoxia-inducible factor-1α (HIF-1α) level, which then downregulated the expression of PD-L1. Our in vitro and in vivo results have confirmed CaO₂@Lipo promoted the degradation of HIF-1α and then downregulated the expression of PD-L1 in cancer cells for avoiding immune escape. Furthermore, to mimicking the clinical protocol of anti-PD-L1 antibodies + chemo-drugs, CaO₂@Lipo was combined with doxorubicin (DOX) to investigate the tumor inhibition efficiency. We found CaO₂@Lipo enhanced DOX-induced immunogenic cell death (ICD) effect, which then promoted the infiltration of T cells, strengthened the blocking effect, and thus provided an effective means to overcome the traditional immune checkpoint blockade treatment.

Tumor hypoxia has been considered to induce tumor cell resistance to radiotherapy and anticancer chemotherapy, as well as predisposing for increased tumor metastases. Therefore, strategies for the eradication of the hypoxic tumor are highly desirable. Photodynamic therapy (PDT) is a new technique that can be used to treat tumors using laser irradiation to photochemically activate a photosensitizer. Compared to traditional radiotherapy and chemotherapy, photodynamic therapy has many advantages, such as good selectivity, low toxicity, and less trauma and resistance. However, PDT is oxygen-dependent, and the lack of oxygen in hypoxic tumors renders photodynamic therapy ineffective. Cyanobacteria, the earliest photosynthetic oxygen-generating organisms, can utilize water as an electron donor to reduce CO₂ into organic carbon compounds along with continuously releasing oxygen under sunlight. Inspired by this, herein, cyanobacteria were used as a living carrier of photosensitizer conjugated upconversion nanoparticles (UCNP) to construct a self-supplying oxygen PDT system. Improvement in the PDT efficiency for hypoxic tumors can be achieved as a result of in situ oxygen production by cyanobacteria under near-infrared (NIR) light using UCNP as a light harvesting antenna. A successful demonstration of this concept would be of great significance and could open the door to a new generation of carrier systems in the field of hypoxia-targeted drug transport platforms.