Kuwentrai Chaiyaporn, Tang Weilong, Lin Xuansheng, Chi Teng, Liu Dongping, Song Erwei, Webber Matthew J, Huang Jian-Dong, Ye Zhou
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, SAR, China.
Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, University of Hong Kong, Hong Kong, SAR, China.
J Control Release. 2025 Aug 10;384:113897. doi: 10.1016/j.jconrel.2025.113897. Epub 2025 May 29.
Tertiary lymphoid structures (TLSs) in the tumor microenvironment are associated with improved cancer prognosis and enhanced immune checkpoint blockade (ICB) responses. In this study, an injectable hydrogel-based drug formulation is developed to stimulate TLSs formation in a B16-OVA melanoma mouse model. A hydrogel, termed HA-CPP⸦CB[8], is formed by supramolecular interactions between 4-(4-chlorophenyl)pyridine modified hyaluronic acid (HA-CPP) and cucurbit[8]uril (CB[8]). The results reveal that a single injection of HA-CPP⸦CB[8] hydrogel containing the CXCL13 chemokine and LIGHT cytokine effectively increases TLSs density, facilitates mature TLSs formation, suppresses tumor growth, and extends survival. Importantly, the hydrogel treatment also up-regulates the number of antigen-specific T-cells in the secondary lymphoid organs. Furthermore, combination of the hydrogel-based drug formulation and the anti-PD1 ICB therapy results in increased tumor suppression, improved survival rates, and strengthened TLSs formation, ultimately contributing to B16-OVA melanoma eradication. In conclusion, this study demonstrates the potential application of hydrogel-based drug carriers as synthetic immune niche scaffolds for promoting mature-like TLSs formation within the B16-OVA melanoma tumor microenvironment, offering a promising strategy for advancing tumor immunotherapy.
肿瘤微环境中的三级淋巴结构（TLSs）与癌症预后改善及免疫检查点阻断（ICB）反应增强相关。在本研究中，开发了一种基于可注射水凝胶的药物制剂，以在B16-OVA黑色素瘤小鼠模型中刺激TLSs形成。一种名为HA-CPP⸦CB[8]的水凝胶由4-(4-氯苯基)吡啶修饰的透明质酸（HA-CPP）与葫芦[8]脲（CB[8]）之间的超分子相互作用形成。结果显示，单次注射含有CXCL13趋化因子和LIGHT细胞因子的HA-CPP⸦CB[8]水凝胶可有效增加TLSs密度，促进成熟TLSs形成，抑制肿瘤生长并延长生存期。重要的是，水凝胶治疗还上调了二级淋巴器官中抗原特异性T细胞的数量。此外，基于水凝胶的药物制剂与抗PD1 ICB疗法联合使用可增强肿瘤抑制作用，提高生存率并加强TLSs形成，最终有助于根除B16-OVA黑色素瘤。总之，本研究证明了基于水凝胶的药物载体作为合成免疫微环境支架在促进B16-OVA黑色素瘤肿瘤微环境中形成成熟样TLSs的潜在应用，为推进肿瘤免疫治疗提供了一种有前景的策略。
