Although immune checkpoint blockade has shown initial success for various cancers, only a small subset of patients benefits from this therapy. Some chemotherapeutic drugs have been reported to induce antitumor T cell responses, prompting a number of clinical trials on combination chemoimmunotherapy. However, how to achieve potent immune activation with traditional chemotherapeutics in a manner that is safe, effective, and compatible with immunotherapy remains unclear. We show that high-density lipoprotein-mimicking nanodiscs loaded with doxorubicin (DOX), a widely used chemotherapeutic agent, can potentiate immune checkpoint blockade in murine tumor models. Delivery of DOX via nanodiscs triggered immunogenic cell death of cancer cells and exerted antitumor efficacy without any overt off-target side effects. "Priming" tumors with DOX-carrying nanodiscs elicited robust antitumor CD8⁺ T cell responses while broadening their epitope recognition to tumor-associated antigens, neoantigens, and intact whole tumor cells. Combination chemoimmunotherapy with nanodiscs plus anti-programmed death 1 therapy induced complete regression of established CT26 and MC38 colon carcinoma tumors in 80 to 88% of animals and protected survivors against tumor recurrence. Our work provides a new, generalizable framework for using nanoparticle-based chemotherapy to initiate antitumor immunity and sensitize tumors to immune checkpoint blockade.

中文翻译：

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通过基于纳米圆盘的联合化学免疫疗法消除已形成的肿瘤。


尽管免疫检查点阻断已在多种癌症中取得了初步成功，但只有一小部分患者从这种疗法中受益。据报道，一些化疗药物可诱导抗肿瘤 T 细胞反应，促使开展了一系列联合化学免疫疗法的临床试验。然而，如何以安全、有效且与免疫疗法兼容的方式利用传统化疗药物实现有效的免疫激活仍不清楚。我们发现，装载有广泛使用的化疗药物阿霉素（DOX）的高密度脂蛋白模拟纳米盘可以增强小鼠肿瘤模型中的免疫检查点阻断。通过纳米圆盘递送 DOX 引发癌细胞的免疫原性细胞死亡，并发挥抗肿瘤功效，且没有任何明显的脱靶副作用。用携带 DOX 的纳米圆盘“引发”肿瘤可引发强大的抗肿瘤 CD8 ⁺ T 细胞反应，同时扩大其对肿瘤相关抗原、新抗原和完整肿瘤细胞的表位识别。化学免疫疗法与纳米圆盘联合抗程序性死亡1疗法诱导80%至88%的动物中已形成的CT26和MC38结肠癌肿瘤完全消退，并保护幸存者免遭肿瘤复发。我们的工作提供了一个新的、可推广的框架，用于使用基于纳米颗粒的化疗来启动抗肿瘤免疫并使肿瘤对免疫检查点封锁敏感。