Xin Youtao, Yu Yunjian, Wu Mengdi, Su Meihui, Elsabahy Mahmoud, Qu Xiongwei, Gao Hui
State Key Laboratory of Separation Membranes and Membrane Processes & Key Laboratory of Hollow Fiber Membrane Materials and Membrane Processes (MOE) & Tianjin Key Laboratory of Hollow Fiber Membrane Materials and Processes, School of Materials Science and Engineering, Tiangong University, Tianjin 300387, China.
State Key Laboratory of Separation Membranes and Membrane Processes & Key Laboratory of Hollow Fiber Membrane Materials and Membrane Processes (MOE) & Tianjin Key Laboratory of Hollow Fiber Membrane Materials and Processes, School of Materials Science and Engineering, Tiangong University, Tianjin 300387, China.
J Control Release. 2025 Mar 10;379:574-591. doi: 10.1016/j.jconrel.2025.01.048. Epub 2025 Jan 24.
Clinical benefits of immunotherapy in colorectal cancer (CRC) are limited due to the low immunogenicity and immunosuppressive tumor microenvironment. Fusobacterium nucleatum (Fn) is discovered to colonize CRC tumors and dampen immunotherapy by fostering an immunosuppressive TME. Herein, a controllable "Shielding-deshielding" N-acetylgalactosamine (GalNAc)-derived photothermal nanotherapeutic is developed to mediate cascade targeting toward tumor and intratumoral Fn for enhanced photothermal-immunotherapy. This nanotherapeutic can in situ generate near infrared-II laser-activatable photothermal agent by reacting with endogenous hydrogen sulfide in CRC. The Schiff bond-tethered hyaluronic acid coating not only facilitates precise localization within CRC but shieldes GalNAc-mediated liver targeting, which can be deshielded upon a slightly acidic TME to anchor Fn by binding to its lectin Fap2. This cascade-targeting nanotherapeutic enables efficacious tumor accumulation and reinforces photothermal therapy (PTT) efficacy. Notably, PTT efficiently induces immunogenic cell death in CRC cells, leading to augmented immunogenicity and CD8 T cell activation. Meanwhile, synchronous eradication of Fn facilitates M1 macrophage polarization, and promotes intratumoral infiltration of CD8 T cell by reducing succinic acid level, thereby further boosting antitumor immunity against both primary and distant tumors. Overall, this study involving cascade targeting-reinforced PTT and intratumoral microorganism modulation offers new insight into effective CRC immunotherapy.
由于免疫原性低和免疫抑制性肿瘤微环境，免疫疗法在结直肠癌（CRC）中的临床益处有限。已发现具核梭杆菌（Fn）定殖于CRC肿瘤中，并通过促进免疫抑制性肿瘤微环境（TME）来削弱免疫疗法。在此，开发了一种可控的“屏蔽-去屏蔽”N-乙酰半乳糖胺（GalNAc）衍生的光热纳米疗法，以介导对肿瘤和肿瘤内Fn的级联靶向，从而增强光热免疫疗法。这种纳米疗法可通过与CRC中的内源性硫化氢反应原位生成近红外-II激光激活的光热剂。席夫碱连接的透明质酸涂层不仅有助于在CRC内精确定位，还屏蔽了GalNAc介导的肝脏靶向，在微酸性TME中可去屏蔽，通过与Fn的凝集素Fap2结合来锚定Fn。这种级联靶向纳米疗法能够实现有效的肿瘤蓄积并增强光热疗法（PTT）疗效。值得注意的是，PTT有效地诱导CRC细胞发生免疫原性细胞死亡，导致免疫原性增强和CD8 T细胞活化。同时，同步清除Fn促进M1巨噬细胞极化，并通过降低琥珀酸水平促进CD8 T细胞在肿瘤内浸润，从而进一步增强对原发性和远处肿瘤的抗肿瘤免疫力。总体而言，这项涉及级联靶向增强PTT和肿瘤内微生物调节的研究为有效的CRC免疫疗法提供了新的见解。
