Abstract：
Oncogene activation and epigenome dysregulation drive tumor initiation and progression, contributing to tumor immune evasion and compromising the clinical response to immunotherapy. Epigenetic immunotherapy represents a promising paradigm in conquering cancer immunosuppression, whereas few relevant drug combination and delivery strategies emerge in the clinic. This study presents a well-designed triune nanomodulator, termed ROCA, which demonstrates robust capabilities in tumor epigenetic modulation and immune microenvironment reprogramming for cancer epigenetic immunotherapy. The nanomodulator is engineered from a nanoscale framework with epigenetic modulation and cascaded catalytic activity, which self-assembles into a nanoaggregate with tumor targeting polypeptide decoration that enables loading of the immunogenic cell death (ICD)-inducing agent. The nanomodulator releases active factors specifically triggered in the tumor microenvironment, represses oncogene expression, and initiates the type 1 T helper (TH1) cell chemokine axis by reversing DNA hypermethylation. This process, together with ICD induction, fundamentally reprograms the tumor microenvironment and significantly enhances the rejuvenation of exhausted cytotoxic T lymphocytes (CTLs, CD8+ T cells), which synergizes with the anti-PD-L1 immune checkpoint blockade and results in a boosted antitumor immune response. Furthermore, this strategy establishes long-term immune memory and effectively prevents orthotopic colon cancer relapse. Therefore, the nanomodulator holds promise as a standalone epigenetic immunotherapy agent or as part of a combination therapy with immune checkpoint inhibitors in preclinical cancer models, broadening the array of combinatorial strategies in cancer immunotherapy.
摘要：
癌基因激活和表观基因组失调驱动肿瘤发生和进展，有助于肿瘤免疫逃避并损害对免疫疗法的临床反应。表观遗传免疫疗法代表了克服癌症免疫抑制的一个有希望的范例。而临床上很少出现相关的药物组合和给药策略。本研究提出了一种精心设计的三位一体纳米调制器，叫做ROCA,这表明在肿瘤表观遗传调节和免疫微环境重编程的癌症表观遗传免疫治疗的强大能力。纳米调节剂是由具有表观遗传调制和级联催化活性的纳米级框架设计而成的，其自组装成具有肿瘤靶向多肽修饰的纳米聚集体,其使得能够装载免疫原性细胞死亡(ICD)诱导剂。纳米调节剂释放在肿瘤微环境中特异性触发的活性因子，抑制癌基因表达，并通过逆转DNA超甲基化启动1型T辅助细胞（TH1）趋化因子轴。这个过程,与ICD感应一起，从根本上重新编程肿瘤微环境，并显着增强耗尽的细胞毒性T淋巴细胞的复兴（CTL，CD8+T细胞），与抗PD-L1免疫检查点阻断协同作用，并导致增强的抗肿瘤免疫反应。此外，该策略建立了长期免疫记忆,并有效防止原位结肠癌复发.因此,纳米调节剂有望作为独立的表观遗传免疫治疗剂或作为临床前癌症模型中与免疫检查点抑制剂联合治疗的一部分，拓宽了癌症免疫治疗中的组合策略。
