tRNA-derived fragments (tRFs) play a crucial role in tumor progression. However, whether and how tRFs regulate the immune response in esophageal squamous cell carcinoma (ESCC) and their potential clinical applications remain unclear. tRF-22 enhances myeloid-derived suppressor cells (MDSCs) infiltration via a tRF-22–hnRNPAB–TGFβ2 axis, which in turn leads to the suppression of CD8+ T cells. Targeting tRF-22 or TGFβ2 reactivates antitumor immunity and synergistically enhances the effectiveness of anti-PD1 therapy in ESCC. Patients with lower tRF-22 levels exhibit better responses to immunotherapy and longer progression-free survival in our ESCC-ICB cohort.