tRNA‐Derived Fragment tRF‐22 Promotes Immunosuppression by Inhibiting HnRNPAB Ubiquitination in Esophageal Squamous Cell Carcinoma

Abstract Small proportions of patients with esophageal squamous cell carcinoma (ESCC) benefit from immune checkpoint blockade therapy, making it urgent to identify factors that limit its effectiveness. It is found that tRF‐22 , a small RNA derived from tRNA GlnCTG/TTG , promotes an immunosuppressive tumor microenvironment. High tRF‐22 expression is associated with worse prognosis in ESCC. tRF‐22 shapes immunosuppression by increasing polymorphonuclear myeloid‐derived suppressor cells (PMN‐MDSCs) infiltration and suppressing CD8 + T cells. Mechanistically, it binds to Lys91 on hnRNPAB, inhibiting its ubiquitination by TRIM25, leading to the stabilization of hnRNPAB, which activates TGFB2 transcription. Accumulated TGFβ2 promotes MDSCs generation to drive immunosuppression in ESCC. Using tRF‐22 antagomir or TGFβ signaling blockade in combination with anti‐PD1 therapy enhances immune response and reduces tumor growth. Overall, a tRF‐22 –hnRNPAB–TGFβ2–PMN‐MDSCs–CD8 + T cell pathway is identified that drives immunosuppression and tumor growth. Targeting tRF‐22 may be a promising strategy to improve immunotherapy efficacy in ESCC.