Giving T cells a break: controlled physical barrier created to boost cancer immunotherapy

Chinese researchers recently reported a method for improving cancer immunotherapy efficacy by giving T cells—the body's cancer- and infection-fighting white cells—a rest.

Cancer immunotherapies such as immune checkpoint blockade and chimeric antigen receptor T cell therapy have reshaped modern oncology. However, T cells rapidly become exhausted after infiltrating tumor tissue, causing them to lose their ability to kill cancer cells. This exhaustion is driven in part by persistent interactions between T cells and tumor cells, involving multiple immunosuppressive signaling pathways that apply brakes to the immune response.

In response to this problem, Prof. LIANG Xingjie's team from the National Center for Nanoscience and Technology of the Chinese Academy of Sciences (CAS), along with Prof. GONG Ningqiang from the University of Science and Technology of China of CAS, has developed a biomimetic physical barrier (BPB) that temporarily blocks T cell–tumor cell interactions, thereby delaying T cell exhaustion and enabling a stronger, more sustained immune response. The study was published in PNAS.

The breakthrough is based on the observation that fibrotic barriers in solid tumors physically hinder interactions between immune cells and tumor cells. 

"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?" said Prof. LIANG. 

To realize this concept, the researchers 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—from a liquid-like solution ("sol") into a semi-solid, jelly-like material ("gel")—at body temperature. The gel formed a temporary "protective zone" that physically blocked T cell–tumor cell interactions, delaying T cell exhaustion and allowing T cells to accumulate in a more functional state. After enough T cells accumulated, a low dose of near-infrared light was applied to trigger the BPB's reverse gel-to-sol transition, 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.

This study also uncovered how the BPB exerts its therapeutic effect. Specifically, after BPB is formed, more stem-like progenitor exhausted T (T_pex) cells accumulated in the tumor tissue. Once the BPB was removed, these T_pex 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 toward 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'," said Prof. GONG. "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."

The controlled modulation of the T cell–tumor cell interaction represents a promising step toward sustainable cancer immunotherapy. The BPB strategy can potentially be combined with a variety of other immunotherapeutic approaches to enhance treatment efficacy.