Tumors Induce T Cell Senescence Via Extracellular Vesicles Containing PD-L1

Recently, the latest research results published by researchers from the Saint Louis University School of Medicine in the journal Science Translational Medicine showed that cancer cells can produce tumor-derived extracellular vesicles (tEVs) containing PD-L1, causing PD-L1 to activate CREB and STAT signals, leading to lipid metabolism reprogramming of T cells. This induces T cell senescence and achieves immunosuppression. Blocking this process is expected to improve the sensitivity of solid tumors to immunotherapy such as PD-L1 inhibitors.

The researchers first extracted tEVs from a variety of cancer cell lines (melanoma, lung cancer and breast cancer) and marked them with molecular markers. In vitro co-culture experiments confirmed that tEVs can interact with CD4+T cells and localize to the surface of T cells. When they were injected into mice, tEVs also moved to the spleen and blood with T cells and could significantly inhibit T cell proliferation, while EVs of ordinary cells did not cause similar phenomena.

Further analysis showed that tEVs did not cause T cell apoptosis or exhaustion, but could induce T cell senescence. It is manifested as increased expression of senescence-associated β-galactosidase (SA-β-gal) and upregulated expression of cell cycle molecules. After knocking out the expression of PD-L1 in cancer cell lines, the effect of tEVs produced by them on inducing T cell senescence was significantly weakened. On this basis, the addition of PD-L1 inhibitors can more effectively prevent T cell senescence, and the use of recombinant human PD-L1 treatment can reproduce the induced senescence of T cells. The researchers also specifically confirmed that other common components of tEVs, such as cAMP, are not involved in inducing T cell senescence.

Figure 1. PD-L1 in tEVs is responsible for the induction of T cell senescence. (Ma F, et al., 2025)

Therefore, tEVs containing PD-L1 are the most critical factor in inducing T cell aging. Next, we need to see how it works. The researchers first found that tEVs containing PD-L1 can directly induce DNA chain breaks in CD4+T cells and upregulate the phosphorylation levels of ATM and downstream DNA damage response-related proteins such as H2AX and CHK2. T cell aging is accelerated by inducing DNA damage response. The phosphorylation level of CREB protein is also similarly upregulated.

The process in which CREB participates is the second mechanism by which tEVs containing PD-L1 induce T cell aging - leading to lipid metabolism reprogramming. After treatment with tEVs, the cholesterol and phospholipid metabolism capacity of T cells increased significantly, resulting in the accumulation of a large number of lipid droplets in the cells. The changes in the expression levels of related genes in this process are all precisely regulated by the coordinated efforts of CREB and STAT1/3 signals. ATM signals are also involved. The surge in lipid metabolism rate is also the core link in inducing T cell aging.

Therefore, in order to cut off the negative effects of tEVs containing PD-L1, intervention can be carried out in each of the above links. For example, using simvastatin to block cholesterol synthesis, using special inhibitors to affect lipid droplet formation (Avasimibe), and then tracing back to inhibit CREB signaling, and even further inhibiting the ability of cancer cells to produce tEVs, can effectively prevent T cells from being induced to age in experiments. Among them, CREB inhibitors and simvastatin treatments can clearly synergize with PD-L1 inhibitor treatment and adoptive cell therapy, and have the potential to become a combination therapy.