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

## TL;DR

A small RNA called tRF-22 helps cancer avoid the immune system in esophageal cancer by stabilizing a protein and boosting immune-suppressing cells.

## Contribution

Identifies tRF-22 as a novel driver of immunosuppression in ESCC through hnRNPAB stabilization and TGFβ2 activation.

## Key findings

- tRF-22 inhibits hnRNPAB ubiquitination, stabilizing it and promoting TGFβ2 expression.
- High tRF-22 levels correlate with poor prognosis and increased immunosuppressive cells in ESCC.
- Blocking tRF-22 or TGFβ signaling improves anti-PD1 therapy response in ESCC.

## 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 tRNAGlnCTG/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.

tRF‐22 fosters an immunosuppressive and pro‐oncogenic tumor microenvironment in ESCC by stabilizing hnRNPAB against TRIM25‐mediated ubiquitination and enhancing TGFβ2 expression, which increases PMN‐MDSCs infiltration and suppresses CD8+ T cells. Targeting tRF‐22 or blocking TGFβ signalling improves anti‐PD1 response, offering a promising therapeutic strategy to enhance immunotherapy efficacy in ESCC.