m ¹ A‐Dependent TRMT6/61A‐ARG2 Axis Drives Protumorigenic Senescence by Remodeling the Tumor Microenvironment

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 N¹-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.