Tumor-associated bacteria (TAB) play a critically important role in regulating the microenvironment of a tumor, which consequently greatly deteriorates the therapeutic effects by chemo- and radiotherapy deactivation and, more considerably, leads to substantial immunosuppression. On the contrary, herein we propose a nanocatalytic tumor-immunotherapeutic modality based on the bacteria disintegration by bacteria-specific oxidative damage under magnetic hyperthermia for highly effective immune response activation-promoted tumor regression. A monodispersed and superparamagnetic nanocatalytic medicine modified by arginyl-glycyl-aspartic acid (RGD) and (3-carboxypropyl)triphenylphosphonium bromide (TPP), named as MNP-RGD-TPP herein, has been synthesized, which features selective accumulation at the TAB by the electrostatic affinity, enabling effective TAB disintegration by the nanocatalytic Fenton reaction producing abundant cytotoxic hydroxyl radicals in situ under alternating magnetic field-induced hyperthermia. More importantly, the lipopolysaccharide has been metabolically secreted from the destructed TAB as pathogen-associated molecular patterns (PAMPs) to M1-polarize tumor-associated macrophages (TAMs) and promote the maturation of dendritic cells (DCs) for innate immuno-response activation of TAMs, followed by cytotoxic T lymphocytes awakening under the PAMPs presentation by the mature DCs against tumor cells. The integrated innate and adaptive immunity activations based on this TAB-promoted nanocatalytic immunomedicine, instead of magnetic heating-induced hyperthermia or the released Fe2+/Fe3+ Fenton agent, has been found to achieve excellent therapeutic efficacy in an orthotopic colorectal cancer model, demonstrating the great potential of such an integrated immunity strategy in clinical tumor immunotherapy.
肿瘤相关细菌在调节肿瘤微环境中起着至关重要的作用，这通过使化疗和放疗失活而严重削弱治疗效果，更显著的是导致显著的免疫抑制。相反，本文提出一种基于磁热疗下细菌特异性氧化损伤导致细菌解体的纳米催化肿瘤免疫治疗模式，以实现高效免疫应答激活并促进肿瘤消退。我们合成了一种经精氨酸-甘氨酸-天冬氨酸（RGD）和（3-羧丙基）三苯基溴化鏻（TPP）修饰的单分散超顺磁性纳米催化药物（命名为MNP-RGD-TPP），该药物通过静电亲和力在肿瘤相关细菌处选择性聚集，在交变磁场诱导的热疗条件下，通过纳米催化芬顿反应原位产生大量细胞毒性羟基自由基，从而实现有效的肿瘤相关细菌解体。更重要的是，被破坏的肿瘤相关细菌代谢分泌脂多糖作为病原体相关分子模式，促使肿瘤相关巨噬细胞向M1型极化，并促进树突状细胞成熟，从而激活肿瘤相关巨噬细胞的先天免疫应答；随后成熟的树突状细胞通过呈递病原体相关分子模式唤醒细胞毒性T淋巴细胞以攻击肿瘤细胞。在这种基于肿瘤相关细菌促进的纳米催化免疫药物（而非磁热诱导的高热或释放的Fe2+/Fe3+芬顿试剂）整合先天性与适应性免疫激活的策略下，原位结直肠癌模型显示出优异的治疗效果，证明了这种综合免疫策略在临床肿瘤免疫治疗中的巨大潜力。
Nanocatalytic bacteria disintegration reverses immunosuppression of colorectal cancer
肿瘤(癌症)患者之家