Guan Meng, Ding Junfeng, Zhu Ge, Mao Kuirong, Meng Xiandi, Cong Xiuxiu, Tan Huizhu, Xin Yanbao, Zhao Mengfei, Li Jiaxuan, Wang Haorui, Lv Yue, Sun Huating, He Chaoliang, Chen Hongmei, Yang Yong-Guang, Song Yanqiu, Zhang Yuning, Sun Tianmeng
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, 130021, China; Cancer Center, The First Hospital of Jilin University, Changchun, Jilin, 130021, China.
CAS Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, Jilin, PR China; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, Anhui, PR China.
Acta Biomater. 2025 Jul 23. doi: 10.1016/j.actbio.2025.07.049.
Triple-negative breast cancer (TNBC), characterized by its heterogeneity and poor clinical prognosis, presents substantial unmet medical needs. Although exciting progress has been made in immunotherapy for TNBC, optimizing the composition of immune cells within the tumor microenvironment (TME) remains a critical challenge. In this study, we demonstrate that CCL25-transduced tumor cells significantly enhance the accumulation of CCR9CD8T cells within tumors, translating into inhibited TNBC tumor growth in vivo. To further exploit this mechanism, we developed an injectable, thermo-responsive hydrogel loaded with CCL25 for intratumoral delivery, aimed at recruiting CCR9 cells into the TME. Our results revealed that the influence of CCL25 on the TME is both dose- and time-dependent, mediated through the precise regulation of CCR9 cells infiltration into tumor tissues. Furthermore, CCL25-loaded hydrogel, when administered at an appropriate dose and timing, could enhance the therapeutic response to PD-1 inhibitors, credited to the activation of a T cell-dependent antitumor immunity. This innovative approach not only provides deeper insights into the role of the chemokine system in tumor biology but also suggests a promising strategy for enhancing the efficacy of TNBC immunotherapy. The potential of hydrogel-based chemokine delivery systems to remodel the TME could have significant implications for future cancer treatment. STATEMENT OF SIGNIFICANCE: In our study, we developed a thermo-responsive injectable hydrogel for intratumoral delivery of CCL25. Our findings demonstrate that CCL25@gel promotes the infiltration of CCR9CD8T cells into the tumor microenvironment in a dose- and time-dependent manner. Notably, at an optimal dose and administration schedule, CCL25@gel significantly enhances the therapeutic response to PD-1 inhibitors, thereby improving the efficacy of immunotherapy in triple-negative breast cancer (TNBC). These results highlight the potential of CCL25 in modulating the immune landscape of the tumor microenvironment and emphasize the importance of optimizing key delivery parameters-dose, timing, and frequency-to maximize therapeutic benefits. Moreover, this work provides valuable insights into chemokine-based immunotherapy for TNBC, offering new avenues for more effective treatment strategies.
三阴性乳腺癌（TNBC）具有异质性且临床预后较差，存在大量未满足的医疗需求。尽管TNBC免疫治疗已取得令人振奋的进展，但优化肿瘤微环境（TME）中免疫细胞的组成仍然是一项关键挑战。在本研究中，我们证明经CCL25转导的肿瘤细胞可显著增强肿瘤内CCR9⁺CD8⁺T细胞的聚集，进而在体内抑制TNBC肿瘤生长。为进一步利用这一机制，我们开发了一种负载CCL25的可注射热敏水凝胶用于瘤内递送，旨在将CCR9⁺细胞招募至TME。我们的结果显示，CCL25对TME的影响具有剂量和时间依赖性，是通过精确调节CCR9⁺细胞浸润肿瘤组织来介导的。此外，负载CCL25的水凝胶在适当剂量和时间给药时，可增强对PD - 1抑制剂的治疗反应，这归功于T细胞依赖性抗肿瘤免疫的激活。这种创新方法不仅为趋化因子系统在肿瘤生物学中的作用提供了更深入的见解，还为提高TNBC免疫治疗疗效提出了一种有前景的策略。基于水凝胶的趋化因子递送系统重塑TME的潜力可能对未来癌症治疗具有重要意义。重要性声明：在我们的研究中，我们开发了一种用于瘤内递送CCL25的热敏可注射水凝胶。我们的研究结果表明，CCL25@凝胶以剂量和时间依赖性方式促进CCR9⁺CD8⁺T细胞浸润肿瘤微环境。值得注意的是，在最佳剂量和给药方案下，CCL25@凝胶显著增强对PD - 1抑制剂的治疗反应，从而提高三阴性乳腺癌（TNBC）免疫治疗的疗效。这些结果突出了CCL25在调节肿瘤微环境免疫格局方面的潜力，并强调了优化关键递送参数——剂量时间和频率——以最大化治疗益处的重要性。此外，这项工作为TNBC基于趋化因子的免疫治疗提供了有价值的见解，为更有效的治疗策略开辟了新途径。
