Yang Yuanyuan, Zhang Bo, Xu Yangtao, Zhu Wenxiang, Zhu Zinian, Zhang Xibo, Wu Wenze, Chen Jierong, Yu Zhiqiang
Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, Dongguan Key Laboratory of Precision Diagnosis and Treatment for Tumors, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Dongguan, 523058, China.
Jingzhou Central Hospital, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, 434020, China.
Bioact Mater. 2024 Aug 31;42:178-193. doi: 10.1016/j.bioactmat.2024.08.028. eCollection 2024 Dec.
Low tumor immunogenicity, immunosuppressive tumor microenvironment, and bacterial infections have emerged as significant challenges in postsurgical immunotherapy and skin regeneration for preventing melanoma recurrence. Herein, an immunotherapeutic hydrogel booster (GelMA-CJCNPs) was developed to prevent postoperative tumor recurrence and promote wound healing by incorporating ternary carrier-free nanoparticles (CJCNPs) containing chlorine e6 (Ce6), a BRD4 inhibitor (JQ1), and a glutaminase inhibitor (C968) into methacrylic anhydride-modified gelatin (GelMA) dressings. GelMA-CJCNPs reduced glutathione production by inhibiting glutamine metabolism, thereby preventing the destruction of reactive oxygen species generated by photodynamic therapy, which could amplify oxidative stress to induce severe cell death and enhance immunogenic cell death. In addition, GelMA-CJCNPs reduced M2-type tumor-associated macrophage polarization by blocking glutamine metabolism to reverse the immunosuppressive tumor microenvironment, recruiting more tumor-infiltrating T lymphocytes. GelMA-CJCNPs also downregulated IFN-γ-induced expression of programmed cell death ligand 1 to mitigate acquired immune resistance. Benefiting from the amplified systemic antitumor immunity, GelMA-CJCNPs markedly inhibited the growth of both primary and distant tumors. Moreover, GelMA-CJCNPs demonstrated satisfactory photodynamic antibacterial effects against infections, thereby promoting postsurgical wound healing. Hence, this immunotherapeutic hydrogel booster, as a facile and effective postoperative adjuvant, possesses a promising potential for inhibiting tumor recurrence and accelerating skin regeneration.
低肿瘤免疫原性、免疫抑制性肿瘤微环境和细菌感染已成为术后免疫治疗和皮肤再生中预防黑色素瘤复发的重大挑战。在此，通过将含有氯e6（Ce6）、一种BRD4抑制剂（JQ1）和一种谷氨酰胺酶抑制剂（C968）的无载体三元纳米颗粒（CJCNPs）掺入甲基丙烯酸酐修饰的明胶（GelMA）敷料中，开发了一种免疫治疗水凝胶增强剂（GelMA-CJCNPs），以预防术后肿瘤复发并促进伤口愈合。GelMA-CJCNPs通过抑制谷氨酰胺代谢来减少谷胱甘肽的产生，从而防止光动力疗法产生的活性氧被破坏，这可以放大氧化应激以诱导严重的细胞死亡并增强免疫原性细胞死亡。此外，GelMA-CJCNPs通过阻断谷氨酰胺代谢来减少M2型肿瘤相关巨噬细胞极化，以逆转免疫抑制性肿瘤微环境，招募更多的肿瘤浸润性T淋巴细胞。GelMA-CJCNPs还下调了IFN-γ诱导的程序性细胞死亡配体1的表达，以减轻获得性免疫抗性。受益于增强的全身抗肿瘤免疫力，GelMA-CJCNPs显著抑制原发性和远处肿瘤的生长。此外，GelMA-CJCNPs对感染表现出令人满意的光动力抗菌作用，从而促进术后伤口愈合。因此，这种免疫治疗水凝胶增强剂作为一种简便有效的术后佐剂，在抑制肿瘤复发和加速皮肤再生方面具有广阔的应用前景。
