biostudies-literatureMa SNIDA NIH HHSNIAID NIH HHSNHLBI NIH HHSNCI NIH HHSNINDS NIH HHSNational Institutes of HealthORFDO NIH HHSLeukemia and Lymphoma Society255-266https://www.ebi.ac.uk/biostudies/studies/S-EPMC10150872biostudies-literatureUnknown24(2)Despite tumor-associated macrophages (TAMs) playing a key role in shaping the tumor microenvironment (TME), the mechanisms by which TAMs influence the TME and contribute to cancer progression remain unclear. Here, we show that the N⁶-methyladenosine reader YTHDF2 regulates the antitumor functions of TAMs. YTHDF2 deficiency in TAMs suppressed tumor growth by reprogramming TAMs toward an antitumoral phenotype and increasing their antigen cross-presentation ability, which in turn enhanced CD8⁺ T cell-mediated antitumor immunity. YTHDF2 deficiency facilitated the reprogramming of TAMs by targeting interferon-γ-STAT1 signaling. The expression of YTHDF2 in TAMs was regulated by interleukin-10-STAT3 signaling. Selectively targeting YTHDF2 in TAMs using a Toll-like receptor 9Nature immunologyYTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8⁺ T cells.PMC10150872R01 CA26645775N99020D00005R01 NS106170P01 CA163205R01 CA265095R35 CA210087R21 CA22340075N95020D00005U19 CA264512R01 CA24755075N93022D0000575N92020D000051364-19R01 AI12958275N93023D00005He CMa SBissonnette MBZhang JChen JSun BDuan SHan JYu JCaligiuri MABarr TKortylewski MfalseYTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8⁺ T cells.Despite tumor-associated macrophages (TAMs) playing a key role in shaping the tumor microenvironment (TME), the mechanisms by which TAMs influence the TME and contribute to cancer progression remain unclear. Here, we show that the N⁶-methyladenosine reader YTHDF2 regulates the antitumor functions of TAMs. YTHDF2 deficiency in TAMs suppressed tumor growth by reprogramming TAMs toward an antitumoral phenotype and increasing their antigen cross-presentation ability, which in turn enhanced CD8⁺ T cell-mediated antitumor immunity. YTHDF2 deficiency facilitated the reprogramming of TAMs by targeting interferon-γ-STAT1 signaling. The expression of YTHDF2 in TAMs was regulated by interleukin-10-STAT3 signaling. Selectively targeting YTHDF2 in TAMs using a Toll-like receptor 92023-01-01T00:00:00Z2023 Feb2026-05-29T03:05:54.826Z2025-02-19T02:39:01.688ZS-EPMC101508723665823710.1038/s41590-022-01398-6