He Huilan, Liu Liang, Zheng Yun, Ji Jinlong, Cao Li, Ye Chunlian, Sun Yu, Zhang Ying, Zhong Zhiyuan
College of Pharmaceutical Sciences and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China.
Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, China.
Adv Sci (Weinh). 2025 Apr;12(16):e2414110. doi: 10.1002/advs.202414110. Epub 2025 Feb 25.
The immunomodulation of the tumor microenvironment is critical for effective cancer immunotherapy, particularly for tumors that exhibit limited responses to conventional treatments. However, current immune agonists developed for tumor immunomodulation face several challenges, such as poor intratumoral retention, inadequate biocompatibility, and restricted cellular targets, which ultimately hamper their therapeutic efficacy and clinical application. In this study, a tumor-adhesive chitosan-tethered immune agonist construct (TACTIC) is introduced, which demonstrates good biocompatibility and robust immunostimulatory effects, enhancing the immunogenicity of tumor cells while simultaneously stimulating pro-inflammatory responses in various immune cell populations. Mechanistic investigations reveal that TACTIC targets multiple signaling pathways, conferring it to effectively remodel the irradiated tumor microenvironment, improve tumor control on murine cancer models post-radiotherapy, and elicit systemic immune responses with memory effects. The findings highlight the potential of TACTIC as a powerful macromolecular immune adjuvant, paving the way for its broader application in innovative cancer immunotherapies.
肿瘤微环境的免疫调节对于有效的癌症免疫治疗至关重要，特别是对于那些对传统治疗反应有限的肿瘤。然而，目前用于肿瘤免疫调节的免疫激动剂面临着几个挑战，如肿瘤内滞留性差、生物相容性不足和细胞靶点受限，这些最终都阻碍了它们的治疗效果和临床应用。在本研究中，引入了一种肿瘤黏附性壳聚糖连接的免疫激动剂构建体（TACTIC），它表现出良好的生物相容性和强大的免疫刺激作用，增强了肿瘤细胞的免疫原性，同时在各种免疫细胞群体中刺激促炎反应。机制研究表明，TACTIC靶向多种信号通路，使其能够有效地重塑受辐射的肿瘤微环境，改善小鼠癌症模型放疗后的肿瘤控制，并引发具有记忆效应的全身免疫反应。这些发现突出了TACTIC作为一种强大的大分子免疫佐剂的潜力，为其在创新癌症免疫治疗中的更广泛应用铺平了道路。
