Age-related decline in CD8+ tissue resident memory T cells compromises antitumor immunity.

Aging compromises antitumor immunity, but the underlying mechanisms remain elusive. Here, we report that aging impairs the generation of CD8⁺ tissue resident memory T (T_RM) cells in nonlymphoid tissues in mice, thus compromising the antitumor activity of aged CD8⁺ T cells, which we also observed in human lung adenocarcinoma. We further identified that the apoptosis regulator BFAR was highly enriched in aged CD8⁺ T cells, in which BFAR suppressed cytokine-induced JAK2 signaling by activating JAK2 deubiquitination, thereby limiting downstream STAT1-mediated T_RM reprogramming. Targeting BFAR either through Bfar knockout or treatment with our developed BFAR inhibitor, iBFAR2, rescued the antitumor activity of aged CD8⁺ T cells by restoring T_RM generation in the tumor microenvironment, thus efficiently inhibiting tumor growth in aged CD8⁺ T cell transfer and anti-programmed cell death protein 1 (PD-1)-resistant mouse tumor models. Together, our findings establish BFAR-induced T_RM restriction as a key mechanism causing aged CD8⁺ T cell dysfunction and highlight the translational potential of iBFAR2 in restoring antitumor activity in aged individuals or patients resistant to anti-PD-1 therapy.