# m1A‐Dependent TRMT6/61A‐ARG2 Axis Drives Protumorigenic Senescence by Remodeling the Tumor Microenvironment

## TL;DR

This study shows how a specific tRNA modification pathway promotes cancer growth by triggering a harmful cellular aging process.

## Contribution

The discovery of an m1A-dependent TRMT6/61A-ARG2 axis as a driver of pro-tumorigenic senescence in colorectal cancer.

## Key findings

- TRMT6/TRMT61A tRNA m1A methylation enhances ARG2 translation in colorectal cancer cells.
- ARG2 activation promotes SASP and reprograms the tumor microenvironment to support cancer progression.
- The TRMT6-ARG2 axis represents a novel target for senomorphic therapies.

## Abstract

Cellular senescence, a fundamental hallmark of aging, plays a paradoxical, often pro‐tumorigenic role in cancer. This malignancy is largely driven by the senescence‐associated secretory phenotype (SASP), yet the mechanisms that govern the production of a pro‐tumorigenic SASP remain poorly understood. This study uncovers an epitranscriptomic axis in colorectal cancer (CRC) where the TRMT6/TRMT61A tRNA N
1‐methyladenosine (m1A) methyltransferase complex is aberrantly elevated, driving a senescent state in malignant cells. Mechanistically, TRMT6/61A‐dependent m1A deposition on specific tRNAs enhances the translational efficiency of their cognate codons. This codon‐biased translational control selectively boosts the synthesis of ARG2. Accumulation of ARG2 subsequently activates mTOR and NF‐κB signaling and thereby establishes a robust SASP, which actively reprograms the tumor microenvironment by promoting the growth and invasiveness of neighboring cancer cells, activating cancer‐associated fibroblasts, and polarizing immunosuppressive M2 macrophages. Collectively, these findings define the TRMT6/61A‐ARG2 pathway as a driver for pro‐tumorigenic senescence in an m1A‐dependent manner, revealing a new layer of translational control in aging‐associated pathology and offering a compelling rationale for developing senomorphic therapies.

Uncovering a new layer of translational control, this study reveals how TRMT6/TRMT61A‐mediated tRNA‐m1A methylation drives pro‐tumorigenic senescence in colorectal cancer. By selectively enhancing ARG2 translation, this epitranscriptomic axis triggers an NF‐κB‐dependent SASP. This program actively remodels the tumor microenvironment to promote malignancy, identifying the TRMT6‐ARG2 axis as a potent target for senomorphic therapy.