YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8+ T cells

Caligiuri and colleagues show that the m(6)A reader YTHDF2 modulates the inflammatory activation and antitumor function of tumor-associated macrophages in part by modulating the stability of Stat1 mRNA. 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 N-6-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-gamma-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 9 agonist-conjugated small interfering RNA reprogrammed TAMs toward an antitumoral phenotype, restrained tumor growth and enhanced the efficacy of PD-L1 antibody therapy. Collectively, our findings describe the role of YTHDF2 in orchestrating TAMs and suggest that YTHDF2 inhibition is an effective approach to enhance cancer immunotherapy.

Automated summary

Caligiuri and colleagues demonstrate that the m(6)A reader YTHDF2 controls the inflammatory activation and antitumor function of tumor-associated macrophages by regulating the stability of Stat1 mRNA. They show that YTHDF2 deficiency in TAMs reprograms them towards an antitumoral phenotype, enhancing their antigen cross-presentation ability and CD8(+) T cell-mediated antitumor immunity. Moreover, targeting YTHDF2 in TAMs using a Toll-like receptor 9 agonist-conjugated small interfering RNA restrains tumor growth and improves the efficacy of PD-L1 antibody therapy. These findings suggest that YTHDF2 inhibition is a promising strategy to enhance cancer immunotherapy.