SHP1 expression in tumor-associated dendritic cells drives immunoevasion via impairing CD8+ memory T cell responses

Despite the achievements of immunotherapy in the treatment of cancer, overcoming the immune resistance is still an unmet challenge. Dendritic cells (DCs) dysfunction plays a pivotal role in tumor immunoevasion. Previous study uncovered that targeting src homologous region 2 protein tyrosine phosphatase (SHP1) improved anti-PD-1 therapy efficacy in breast cancer by reinvigorating DCs, but the detailed mechanisms remained unclear. Here, we investigated the function of SHP1 in enabling tumor immune escape and suppressing memory T cell formation. Deficiency of SHP1 augmented the activation and antigen-presenting function of dendritic cells, which consequently suppressed the growth of B16-F10 and EMT6 models. We validated this enhanced DC-mediated anti-tumor immunity using conditional knockout mice of SHP1. These results suggested that SHP1 acts as a critical promoter of tumor immune escape. Combining transcriptomic analysis with DC-specific SHP1 deletion, we demonstrated that SHP1 deficiency augments DC immunogenicity via the IFN-γ-JAK1/2-STAT1 pathway. Furthermore, SHP1 blockade promoted the generation of central memory CD8⁺ T cells, through upregulating the expression of TCF-1, a transcription factor essential for memory lineage commitment. In summary, our research identifies SHP1 as a critical intracellular checkpoint that promotes tumor immune evasion by concurrently suppressing DC antigen presentation and the formation of central memory CD8⁺ T cells, nominating it as a promising therapeutic target for immunotherapy-resistant cancers.

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