A research team led by Professor Yang Zhen from the Haixia Institute of Flexible Electronics (Future Technology) at Fujian Normal University (FNU) has achieved a major breakthrough in cancer immunotherapy. Their work addresses a critical challenge in the field: tumor cells' ability to evade immune responses through a biomechanics-driven mechanism. By enriching membrane cholesterol and reducing cytoskeletal F-actin levels, tumor cells decrease their cellular rigidity, significantly diminishing the therapeutic efficacy of STING agonists, which are known for their ability to activate T-cell-mediated antitumor immunity.
To overcome this obstacle, Professor Yang Zhen’s team developed a redox-responsive MeβCD-based supramolecular polyrotaxane nanosystem (RDPNs@diABZIs). This innovative nanosystem synergistically enhances STING immune activation and tumor cell mechanical rigidity, thereby improving T-cell-mediated tumor killing. The nanosystem precisely delivers two components to the tumor microenvironment: diABZIs, a STING agonist, and MeβCD, a cholesterol-depleting agent. Together, these components amplify antitumor immune responses at multiple levels.
diABZIs activate STING in antigen-presenting cells, initiating robust T-cell-mediated antitumor immunity.
MeβCD depletes membrane cholesterol, countering the mechanical softness of cancer cells and enhancing cytotoxic T lymphocyte (CTL)-mediated tumor cell killing.
In tumor-bearing mouse models, this nanosystem significantly boosted antitumor immunity, leading to potent tumor regression and maintaining a tumor-free survival state for at least two months. This groundbreaking strategy provides a feasible approach to triggering robust T-cell-mediated antitumor responses and offers new insights into cancer immunotherapy.
The study, titled "Supramolecular polyrotaxane-based nano-theranostics enable cancer-cell stiffening for enhanced T-cell-mediated anticancer immunotherapy," was published in the prestigious journal Nature Communications. Fujian Normal University is the sole affiliated institution for this research. The first author of the paper is Luo Haifen, a 2024 doctoral candidate from the Haixia Institute of Flexible Electronics (Future Technology). The corresponding authors are Professor Yang Zhen and Postdoctoral Researcher Ma Wen, also from the same institute. This work was supported by the National Natural Science Foundation of China, the Natural Science Foundation of Fujian Province, and the Youth Innovation Team Program of Fujian Normal University.
For more details, the full article can be accessed at: https://www.nature.com/articles/s41467-025-57718-5