Zhang Yuxuan, Wang Jinjin, Qing Guangchao, Wang Yongchao, Li Xianlei, Luo Ting, Wang Yi-Feng, Liu Lu, Wang Yufei, Ni Qiankun, Li Shuyi, Chen Junge, Li Fangzhou, Guo Weisheng, Zhang Jinchao, Gong Ningqiang, Liang Xing-Jie
Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Proc Natl Acad Sci U S A. 2025 Jul 15;122(28):e2500589122. doi: 10.1073/pnas.2500589122. Epub 2025 Jul 8.
Cancer immunotherapy has shown tremendous promise in various cancers. However, current strategies, such as immune checkpoint blockade, primarily restore exhausted T cells but provide only transient efficacy, as the rapid clearance of antibodies. Their limited durability is further hindered by persistent T cell-tumor cell interactions that accelerate T cell exhaustion. To prevent T cells from sustained exposure to these interactions, we present a hydrogel-based biomimetic physical barrier (BPB) here to create a "protective zone" for T cells. The BPB temporarily blocks T cell-tumor cell interactions and shields T cells from inactivation and exhaustion, allowing them to accumulate and maintain their functional activity in the tumor microenvironment. After sufficient T cell accumulation, the dismantling of BPB triggered by near-infrared light irradiation-induced gel-sol transition will restore the interaction between T cells and tumor cells. This controlled re-exposure allows the accumulated T cells to attack the tumor cells in a more activated and anti-exhaustion state, maximizing their tumor-killing potential. Moreover, BPB not only enhances immediate tumor regression but also triggers systemic immune activation and durable memory responses, enabling long-term protection against tumor rechallenge and effective control of multifocal tumors. Collectively, our BPB for modulating the T cell-tumor cell interaction has great prospects for advancing cancer immunotherapy.
癌症免疫疗法在各种癌症中已显示出巨大的前景。然而,目前的策略,如免疫检查点阻断,主要是恢复耗竭的T细胞,但由于抗体的快速清除,只能提供短暂的疗效。持续的T细胞与肿瘤细胞的相互作用加速了T细胞的耗竭,进一步阻碍了它们有限的持久性。为了防止T细胞持续暴露于这些相互作用中,我们在此提出一种基于水凝胶的仿生物理屏障(BPB),为T细胞创建一个“保护区”。BPB暂时阻断T细胞与肿瘤细胞的相互作用,保护T细胞不被失活和耗竭,使它们能够在肿瘤微环境中积累并维持其功能活性。在T细胞充分积累后,近红外光照射诱导的凝胶-溶胶转变触发BPB的拆解,将恢复T细胞与肿瘤细胞之间的相互作用。这种可控的再暴露使积累的T细胞能够以更活化和抗耗竭的状态攻击肿瘤细胞,最大限度地发挥其肿瘤杀伤潜力。此外,BPB不仅增强了即时的肿瘤消退,还触发了全身免疫激活和持久的记忆反应,实现了对肿瘤再挑战的长期保护和对多灶性肿瘤的有效控制。总的来说,我们用于调节T细胞与肿瘤细胞相互作用的BPB在推进癌症免疫疗法方面具有广阔的前景。
Proc Natl Acad Sci U S A. 2025-7-15
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