The activation of sequential events in the cancer-immunity cycle (CIC) is crucial for achieving effective antitumor immunity. However, formidable challenges, such as innate and adaptive immune resistance, along with the off-target adverse effects of nonselective immunomodulators, persist. In this study, a tumor-selective nano-regulator named PNBJQ has been presented, focusing on targeting two nonredundant immune nodes: inducing immunogenic cancer cell death and abrogating immune resistance to fully activate endogenous tumor immunity. PNBJQ is obtained by encapsulating the immunomodulating agent JQ1 within a self-assembling system formed by linking a Type-I photosensitizer to polyethylene glycol through a hypoxia-sensitive azo bond. Benefiting from the Type-I photosensitive mechanism, PNBJQ triggers the immunogenic cell death of hypoxic tumors under near-infrared (NIR) light irradiation. This process resolves innate immune resistance by stimulating sufficient cytotoxic T-lymphocytes. Simultaneously, PNBJQ smartly responds to the hypoxic tumor microenvironment for precise drug delivery, adeptly addressing adaptive immune resistance by using JQ1 to downregulate programmed death ligand 1 (PD-L1) and sustaining the response of cytotoxic T lymphocytes. The activatable synergic photoimmunotherapy promotes an immune-promoting tumor microenvironment by activating an iterative revolution of the CIC, which remarkably eradicates established hypoxic tumors and suppresses distal lesions under low light dose irradiation.

中文翻译：

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用智能纳米调节器激活缺氧肿瘤中癌症免疫循环的迭代革命


癌症免疫循环（CIC）中连续事件的激活对于实现有效的抗肿瘤免疫至关重要。然而，巨大的挑战仍然存在，例如先天性和适应性免疫抵抗，以及非选择性免疫调节剂的脱靶副作用。在这项研究中，提出了一种名为PNBJQ的肿瘤选择性纳米调节剂，重点针对两个非冗余的免疫节点：诱导免疫原性癌细胞死亡和消除免疫抵抗，以充分激活内源性肿瘤免疫。 PNBJQ 是通过将免疫调节剂 JQ1 封装在自组装系统中而获得的，该自组装系统是通过缺氧敏感的偶氮键将 I 型光敏剂与聚乙二醇连接而形成的。受益于 I 型光敏机制，PNBJQ 在近红外 (NIR) 光照射下触发缺氧肿瘤的免疫原性细胞死亡。该过程通过刺激足够的细胞毒性 T 淋巴细胞来解决先天免疫抵抗。同时，PNBJQ 巧妙地响应缺氧肿瘤微环境以实现精确的药物递送，通过使用 JQ1 下调程序性死亡配体 1 (PD-L1) 并维持细胞毒性 T 淋巴细胞的反应来熟练地解决适应性免疫抵抗。可激活的协同光免疫疗法通过激活CIC的迭代革命来促进免疫促进肿瘤微环境，从而在低光剂量照射下显着根除已建立的缺氧肿瘤并抑制远端病变。