PDF(Pubmed)
Abstract：
Myeloid-derived suppressor cells (MDSCs) have played a significant role in facilitating tumor immune escape and inducing an immunosuppressive tumor microenvironment. Eliminating MDSCs and tumor cells remains a major challenge in cancer immunotherapy. A novel approach has been developed using gemcitabine-celecoxib twin drug-based nano-assembled carrier-free nanoparticles (GEM-CXB NPs) for dual depletion of MDSCs and tumor cells in breast cancer chemoimmunotherapy. The GEM-CXB NPs exhibit prolonged blood circulation, leading to the preferential accumulation and co-release of GEM and CXB in tumors. This promotes synergistic chemotherapeutic activity by the proliferation inhibition and apoptosis induction against 4T1 tumor cells. In addition, it enhances tumor immunogenicity by immunogenic cell death induction and MDSC-induced immunosuppression alleviation through the depletion of MDSCs. These mechanisms synergistically activate the antitumor immune function of cytotoxic T cells and natural killer cells, inhibit the proliferation of regulatory T cells, and promote the M2 to M1 phenotype repolarization of tumor-associated macrophages, considerably enhancing the overall antitumor and anti-metastasis efficacy in BALB/c mice bearing 4T1 tumors. The simplified engineering of GEM-CXB NPs, with their dual depletion strategy targeting immunosuppressive cells and tumor cells, represents an advanced concept in cancer chemoimmunotherapy.
摘要：
骨髓来源的抑制细胞（MDSC）在促进肿瘤免疫逃逸和诱导免疫抑制肿瘤微环境中发挥了重要作用。消除MDSCs和肿瘤细胞仍然是癌症免疫治疗的主要挑战。使用吉西他滨-塞来昔布双药物纳米组装无载体纳米颗粒（GEM-CXBNP）开发了一种新方法，用于乳腺癌化学免疫疗法中MDSC和肿瘤细胞的双重消耗。GEM-CXBNP表现出延长的血液循环，导致GEM和CXB在肿瘤中优先积累和共同释放。这通过对4T1肿瘤细胞的增殖抑制和凋亡诱导来促进协同化疗活性。此外,它通过免疫原性细胞死亡诱导和MDSC诱导的免疫抑制通过消耗MDSC增强肿瘤免疫原性。这些机制协同激活细胞毒性T细胞和自然杀伤细胞的抗肿瘤免疫功能，抑制调节性T细胞的增殖，并促进肿瘤相关巨噬细胞的M2至M1表型复极化，显着增强了携带4T1肿瘤的BALB/c小鼠的整体抗肿瘤和抗转移功效。GEM-CXBNP的简化工程，以免疫抑制细胞和肿瘤细胞为目标的双重消耗策略，代表了癌症化学免疫疗法的先进概念。
