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

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 (m ¹ A) methyltransferase complex is aberrantly elevated, driving a senescent state in malignant cells. Mechanistically, TRMT6/61A‐dependent m ¹ A 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 m ¹ A‐dependent manner, revealing a new layer of translational control in aging‐associated pathology and offering a compelling rationale for developing senomorphic therapies.