The low immunogenicity, insufficient infiltration of T lymphocytes, and dismal response to immune checkpoint blockade therapy pose major difficulties in immunotherapy of pancreatic cancer. Photoimmunotherapy by photodynamic therapy (PDT) can induce an antitumor immune response by triggering immunogenic cell death in the tumor cells. Notwithstanding, PDT‐driven oxygen consumption and microvascular damage can further aggravate hypoxia to exaggerates glycolysis, leading to lactate accumulation and immunosuppressive tumor microenvironment. Herein, a supramolecular prodrug nanoplatform codelivering a photosensitizer and a prodrug of bromodomain‐containing protein 4 inhibitor (BRD4i) JQ1 for combinatory photoimmunotherapy of pancreatic cancer are demonstrated. The nanoparticles are fabricated by host–guest complexation between cyclodextrin‐grafted hyaluronic acid (HA‐CD) and adamantine‐conjugated heterodimers of pyropheophorbide a (PPa) and JQ1, respectively. HA can achieve active tumor targeting by recognizing highly expressed CD44 on the surface of pancreatic tumors. PPa‐mediated PDT can enhance the immunogenicity of the tumor cells and promote intratumoral infiltration of the cytotoxic T lymphocytes. Meanwhile, JQ1 combats PDT‐mediated immune evasion through inhibiting expression of c‐Myc and PD‐L1, which are key regulators of tumor glycolysis and immune evasion. Collectively, this study presents a novel strategy to enhance photoimmunotherapy of the pancreatic cancer by provoking T cells activation and overcoming adaptive immune resistance.

中文翻译：

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前药纳米颗粒调节葡萄糖代谢以促进胰腺癌的光免疫治疗。

免疫原性低，T淋巴细胞浸润不足以及对免疫检查点封锁疗法的反应差，在胰腺癌的免疫疗法中构成了主要困难。通过光动力疗法（PDT）进行的光免疫疗法可以通过触发肿瘤细胞中的免疫原性细胞死亡来诱导抗肿瘤免疫反应。尽管如此，PDT驱动的耗氧量和微血管损伤会进一步加重缺氧，加剧糖酵解，导致乳酸蓄积和免疫抑制性肿瘤微环境。在本文中，展示了用于胰腺癌联合光免疫疗法的超分子前药纳米平台共递送光敏剂和含溴结构域蛋白4抑制剂（BRD4i）JQ1的前药。纳米颗粒是通过环糊精接枝的透明质酸（HA-CD）与焦脱镁叶绿素a（PPa）和JQ1的金刚烷共轭异二聚体之间的客体复合而制备的。HA可通过识别胰腺肿瘤表面上高度表达的CD44来实现主动靶向肿瘤。PPa介导的PDT可以增强肿瘤细胞的免疫原性，并促进细胞毒性T淋巴细胞的肿瘤内浸润。同时，JQ1通过抑制c-Myc和PD-L1的表达来对抗PDT介导的免疫逃避，这是肿瘤糖酵解和免疫逃避的关键调节剂。总体而言，这项研究提出了一种新的策略，可通过激发T细胞活化和克服适应性免疫抵抗来增强胰腺癌的光免疫疗法。