Deciphering the potential role of PGRN in regulating CD8⁺ T cell antitumor immunity

A key factor contributing to resistance in immune checkpoint blockade (ICB) therapies is CD8⁺ T-cell tolerance in the tumor microenvironment (TME), partly resulting from upregulating coinhibitory receptors. Here, we describe the role of PGRN as a coinhibitory molecule that modulates the antitumor response of CD8⁺ T cells, thus presenting a novel immunosuppressive target for lung cancer. The in vivo subcutaneous transplanted lung cancer model showed that PGRN expression was elevated on CD8⁺ T cells that infiltrated transplanted lung cancers. Furthermore, PGRN deficiency was found to specifically encourage the infiltration of CD8⁺ T cells, enhance their proliferation, migration, and activation, and resist apoptosis, ultimately inhibiting tumor growth. This was achieved by PGRN knockout, increasing the production of T cell chemokine CCL3, which boosts the antitumor immune response induced by CD8⁺ T cells. Critically, the PD-L1 inhibitor exhibited a synergistic effect in enhancing the antitumor response in PGRN^-/- mice. In summary, our findings highlight the significance of PGRN as a novel target for boosting CD8⁺ T cells antitumor immunity and its potential to overcome the resistance in ICB therapy.