刺激肿瘤特异性免疫应答用于个性化免疫疗法的自体癌症疫苗具有肿瘤治疗的巨大潜力。然而,由于免疫抑制肿瘤微环境(ITM),其疗效仍欠佳。这里,我们报告了一种新型的基于细菌的自体癌症疫苗,该疫苗采用碳酸钙(CaCO3)生物矿化沙门氏菌(Sal)作为原位癌疫苗生产者和系统ITM调节剂。CaCO3可以很容易地用钙离子载体A23187共负载在Sal表面上,并且这种生物矿化作用不会影响细菌的生物活性。肿瘤内积累后,CaCO3壳在酸性微环境下分解以减弱肿瘤酸度,伴随着Sal和Ca2+/A23187的释放。具体来说,Sal通过诱导癌细胞免疫原性细胞死亡(ICD)并促进肿瘤细胞和树突状细胞(DC)之间的间隙连接形成以促进抗原呈递而充当癌症疫苗生产者。Ca2+,另一方面,在A23187的帮助下内化到各种类型的免疫细胞中,并与Sal协同作用以系统地调节免疫系统,包括DCs成熟,巨噬细胞极化,和T细胞激活。因此,这种生物疫苗通过激发具有完全生物相容性的有效抗肿瘤免疫力,对原发性和转移性肿瘤均具有显着的功效。这项工作证明了生物工程细菌作为增强肿瘤免疫治疗的生物活性疫苗的潜力。
Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy. However, its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment (ITM). Here, we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate (CaCO3) biomineralized Salmonella (Sal) as an in-situ cancer vaccine producer and systematical ITM regulator. CaCO3 can be facilely coated on the Sal surface with calcium ionophore A23187 co-loading, and such biomineralization did not affect the bioactivities of the bacteria. Upon intratumoral accumulation, the CaCO3 shell was decomposed at an acidic microenvironment to attenuate tumor acidity, accompanied by the release of Sal and Ca2+/A23187. Specifically, Sal served as a cancer vaccine producer by inducing cancer cells\' immunogenic cell death (ICD) and promoting the gap junction formation between tumor cells and dendritic cells (DCs) to promote antigen presentation. Ca2+, on the other hand, was internalized into various types of immune cells with the aid of A23187 and synergized with Sal to systematically regulate the immune system, including DCs maturation, macrophages polarization, and T cells activation. As a result, such bio-vaccine achieved remarkable efficacy against both primary and metastatic tumors by eliciting potent anti-tumor immunity with full biocompatibility. This work demonstrated the potential of bioengineered bacteria as bio-active vaccines for enhanced tumor immunotherapy.