Targeting PAR2 reprograms myeloid cells to enhance antigen presentation and potentiate PD-1 checkpoint blockade therapy

Mechanistically, PAR-2 inhibition reshaped the tumor immune microenvironment, notably by reducing the frequency of putative immunosuppressive myeloid cells and increasing the activation of CD8⁺ T cells in tumors and tumor-draining lymph nodes (tDLNs). These cellular changes were accompanied by a shift in the cytokine milieu favoring T helper 1 (Th1)-type cytokines and decreasing immunosuppressive cytokines. Notably, bulk RNA sequencing of myeloid cells suggested that PAR-2 activity prevented effective antigen presentation.

Accordingly, using ex vivo co-culture assays, we demonstrated that the antigen-presenting functions of tumor-associated and draining lymph node CD11c+ dendritic cells were significantly enhanced when mice were treated with the PAR-2 inhibitor I-117.These findings support a model where PAR‑2 inhibition primes tumor antigen presentation and enhances PD‑1 blockade, providing rationale for their combined use in cancer immunotherapy.