A study published in PNAS and led by Prof. LIANG Xingjie's team from the National Center for Nanoscience and Technology of the Chinese Academy of Sciences (CAS) reported a biomimetic physical barrier (BPB) that temporarily blocks T cell-tumor cell interactions, effectively delaying T cell exhaustion and enabling a stronger, more sustained immune response, which represents a step forward for improving cancer immunotherapy outcomes.
Cancer immunotherapies such as immune checkpoint blockade and chimeric antigen receptor T cell therapy have reshaped modern oncology, however, their efficacy in solid tumors remains limited. One major reason is that T cells rapidly become "exhausted" after infiltrating the tumor tissue, losing their ability to kill cancer cells. This exhaustion is driven in part by persistent interactions between T cells and tumor cells, which involve multiple immunosuppressive signaling pathways that apply brakes to the immune response.
Fibrotic barriers in solid tumors physically hinder interactions between immune cells and tumor cells, contributing to immune evasion. "What if we could harness the concept of physical blocking to modulate the immune microenvironment? What if a controllable barrier could regulate the T cell-tumor cell interaction and give T cells a break to delay their exhaustion?" asked Prof. LIANG.
Inspired by fibrotic barriers, in this study, Prof. LIANG's team, together with Prof. GONG Ningqiang from the University of Science and Technology of China of CAS, designed a thermoresponsive hydrogel-based BPB that mimics the fibrotic matrix.
After being injected into the tumor, the BPB underwent a sol-to-gel transition at body temperature, forming a temporary "protective zone" that physically blocks T cells-tumor cell interactions. This delayed T cell exhaustion process and allowed T cells to accumulate in a more functional state. When sufficient T cells were gathered, a mild dose of near-infrared light was applied to trigger the gel-to-sol transition of BPB, removing the barrier and re-exposing the T cells to tumor cells. At this point, the accumulated T cells exhibited enhanced cytotoxic activity and improved antitumor efficacy in multiple tumor models.
Moreover, the researchers uncovered the underlying mechanism of therapeutic effect of BPB. During the BPB construction, more stem-like progenitor exhausted T (Tpex) cells accumulated in the tumor tissue. Once the BPB was removed, these Tpex cells induced a stronger and more sustained immune response against the tumor tissue.
The findings of this study suggest that temporarily blocking T cell-tumor cell interactions can shift the immune response towards a more durable and effective state. The BPB strategy gives the immune system a chance to gather force and preserve strength. "We call this strategy 'immunological rhythm control.' By modulating the interaction between T cells and tumor cells, we intervene in the process of T cell exhaustion and preserve T cell functional activity to achieve a more effective immune response," explained Prof. GONG.
The controlled modulation of the T cell-tumor cell interaction represents a promising step toward sustainable cancer immunotherapy. The BPB strategy can be combined with a variety of other immunotherapeutic approaches in the future to enhance treatment efficacy.
