Extended Data Fig. 10: Working model of aging-induced decline of CD8+ TRM cells in compromising antitumor immunity through BFAR.

In aged CD8⁺ T cells, the stressed environment upregulates the expression of BFAR, which activates USP39 to mediate the deubiquitylation of JAK2. This process results in the suppression of JAK2 downstream signaling, which in turn leads to a decline in CD8⁺ TRM cells and consequently impaired antitumor defensive immunity. In contrast, low level of BFAR in young CD8⁺ T cells result in the activation of JAK2 signaling, which in turn promotes the expression of cytotoxic- and TRM-related genes. This, in turn, promotes the generation of CD8⁺ TRM cells and the enhancement of antitumor defensive immunity. The increased production of cytotoxic cytokine IFNγ also served to reinforce this process, thereby establishing a positive feedback loop in young CD8⁺ T cells. Moreover, targeting BFAR though the compound iBFAR2 specifically reinvigorated aged CD8⁺ T cells by restoring TRM cell subset generation, thus efficiently suppressing tumor growth in aged or PD-1-therapy-resistant individuals.