Only 20–40% of cancer patients show a durable response to immunotherapy. A major reason is immune exhaustion: when immune defenses are mobilized too long, they lose effectiveness. Researchers at the University of Fribourg have discovered that chemokines - small chemical signals - play a crucial role in signaling when to stop. Their findings are published in Science.

Prolonged immune activation can blunt the body’s ability to fight cancer and chronic infections, and how this shutdown is regulated has remained a central question. The immune system relies on specialized lymphocytes to detect and eliminate pathogens and abnormal cells. Among them, CD8+ T cells are essential: they recognize and destroy infected or cancerous cells. But each T cell is tuned to a single, specific target, and those target cells are often extremely rare. Despite these challenges, the immune system is able to respond efficiently.
Dendritic cells help solve this problem by acting as checkpoints: they present clues about invaders and selectively activate only the T cells that can recognize them. That activation mechanism is well known -but until now, it was unclear how the immune response is actively terminated to prevent overactivation.

Chemokines as stop signals
Working with colleagues in Italy and Germany, the Fribourg team showed that chemokines do more than recruit and pair T cells with dendritic cells. According to Prof. Jens Stein (Department of Oncology, Microbiology and Immunology), “We already knew chemokines act as ‘matchmakers,’ connecting CD8+ T cells with dendritic cells to enable activation. What we discovered is that they also function as timers: they trigger separation of dendritic cells from T cells to prevent excessive stimulation. ” Without this stop signal, T cells remain in prolonged contact with dendritic cells and become less effective.

Lab observations vs. in vivo behavior
In vitro, the researchers observed T cells remaining attached to dendritic cells for long periods. These observations, obtained in part using mouse models and cell cultures, enabled a direct comparison of lymphocyte behavior under controlled laboratory conditions and in living organisms. In contrast, in lymph nodes in living organisms, T cells typically detach after a day or two. Lukas Altenburger, a specialist in T cell differentiation, explains the difference: “By comparing the two settings and manipulating chemokine levels while observing cells in real time, we found that chemokines instruct T cells to disengage.”

Medical implications
“This discovery improves our understanding of why lymphocytes can become ineffective from overstimulation in some chronic diseases and cancers,” says Jens Stein. The findings could inform strategies to enhance cancer immunotherapy, refine vaccination approaches, and clarify certain immune dysfunctions.

Lukas M. Altenburger et al. Lymphoid tissue chemokines limit priming duration to preserve CD8+ T cell functionality. Science392,eadq2080(2026). DOI:10.1126/science.adq2080