Chitosan oligosaccharide regulates AMPK and STAT1 pathways synergistically to mediate PD-L1 expression for cancer chemoimmunotherapy.

After regular chemotherapy, the expression of programmed cell death ligand 1 (PD-L1) in almost all kinds of cancers is significantly increased, leading to reduced efficacy of T cell mediated immune killing in tumors. To solve this, a lot of PD-L1 antibodies were produced and used, but their high cost and serious toxic side effects still limit its usage. Recently, small molecule compounds that could effectively regulate PD-L1 expression possess the edges to solve the problems of PD-L1 antibodies. Chitosan oligosaccharide (COS), a biomaterial derived from the N-deacetylation product of chitin, has a broad spectrum of biological activities in treating tumors. However, the mechanism of its anti-cancer effect is still not well understood. Here, for the first time, we clearly identified that COS could inhibit the upregulated PD-L1 expression induced by interferon γ (IFN-γ) in various tumors via the AMPK activation and STAT1 inhibition. Besides, COS itself significantly restricted the growth of CT26 tumors by enhancing the T cell infiltration in tumors. Furthermore, we observed that combining COS with Gemcitabine (GEM), one of the typical chemotherapeutic drugs, leaded to a more remarkable tumor remission. Therefore, it was demonstrated that COS could be used as a useful way to improve the efficacy of existing chemotherapies by effective PD-L1 downregulation.

Injectable and Biodegradable Chitosan Hydrogel-Based Drug Depot Contributes to Synergistic Treatment of Tumors.

Combined therapy provides a more effective method in the treatment of tumors and becomes a research hotspot. To improve treatment outcomes and reduce serious side effects, hydrogel-based local delivery was developed herein to form a drug depot in suit to eliminate tumors. Indocyanine green and imiquimod were coencapsulated in the novel temperature-sensitive chitosan hydrogel. After intratumoral injection of the hydrogel, indocyanine green that accumulated in the tumor area could induce thermal ablation of primary tumors under laser irradiation. In the presence of imiquimod, the immune effects increased the probability of complete ablation of primary tumors and inhibition of metastases. Combined with cyclophosphamide, the enhanced immunological responses would further inhibit tumors and prolong the survival time. In a word, this work offered an excellent local delivery platform that enabled a remarkable combined antitumor strategy and achieved synergistic therapeutic effects.