tRNA m1A modification enhances anti-tumor immunity in macrophages by promoting translation of key interferon associated genes [TAMs bulk RNA-seq]

Tumor-associated macrophages (TAMs) play a crucial role in tumor progression through their recruitment, polarization, and interaction with T cells in the tumor microenvironment (TME). However, the mechanisms underlying the post-transcriptional and translational regulation of TAMs in the TME remain largely unknown. In this study, we investigate the role of tRNA N1-methyladenosine (m1A) modification in controlling the behavior of macrophages in response to TME stimuli. We demonstrate that the m1A “writer” enzymes TRMT61A is highly enriched in the anti-tumoral and phagocytotic TAM subset, and TRMT61A is rapidly downregulated in macrophages upon stimulation with multiple TME components. Macrophage-specific knockout of TRMT61A leads to increased infiltration of TAMs, impaired CD8+ T cell function, and enhanced tumor growth. To further explore the biological effects of m1A deficient macrophages, we performed RNA sequencing analysis of TRMT61A-KO and WT TAMs derived from tumor bearing Trmt61af/fLysmCre and Trmt61af/f mice. The Gene ontology (GO) and Gene set enrichment analysis (GSEA) documented that the interferon response and the STAT1/IL-12 signaling pathway were impaired in TAMs upon TRMT61A deletion, indicating that TRMT61A is critical for macrophages to control interferon responses and exert anti-tumor effect in the TME.