Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells.

Regulatory T (T reg ) cells have an immunosuppressive function and highly express the immune checkpoint receptor PD-1 in the tumor microenvironment; however, the function of PD-1 in tumor-infiltrating (TI) T reg cells remains controversial. Here, we showed that conditional deletion of PD-1 in T reg cells delayed tumor progression. In Pdcd1 fl/fl Foxp3 eGFP-Cre-ERT2(+/-) mice, in which both PD-1-expressing and PD-1-deficient T reg cells coexisted in the same tissue environment, conditional deletion of PD-1 in T reg cells resulted in impairment of the proliferative and suppressive capacity of TI T reg cells. PD-1 antibody therapy reduced the TI T reg cell numbers, but did not directly restore the cytokine production of TI CD8 + T cells in TC-1 lung cancer. Single-cell analysis indicated that PD-1 signaling promoted lipid metabolism, proliferation and suppressive pathways in TI T reg cells. These results suggest that PD-1 ablation or inhibition can enhance antitumor immunity by weakening T reg cell lineage stability and metabolic fitness in the tumor microenvironment.