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Targeting METTL3/m6A/SOCS3 axis reprograms tumor-associated macrophage polarization to potentiate the efficacy of
Gang Wang1, Fangyu Zhou2, Xuefen Yan3
1Department of Hematology, Quzhou People's Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, Gang Wang. No.100 Minjiang Avenue, Kecheng District, Quzhou, Zhejiang, 324000, China. gumpwang@163.com.
Background:
This study investigated the immunomodulatory roles of suppressor of cytokine signaling 3 (SOCS3) in macrophage polarization and cytotoxic T-cell activation within the tumor microenvironment (TME) of multiple myeloma (MM).
Methods:
SOCS3 expression was evaluated in clinical MM specimens and healthy controls. Gain- and loss-of-function assays and a MM cell-macrophage co-culture system were designed to elucidate the effects of SOCS3 on MM cell malignant progression and macrophage polarization. Mechanistic investigations focused on methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) modulation of SOCS3 and regulation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Additionally, the antitumor efficacy of combined SOCS3 overexpression and anti-programmed cell death protein 1 (anti-PD-1) therapy was evaluated in a syngeneic subcutaneous tumor mouse model.
Results:
SOCS3 was downregulated in clinical MM samples and cell lines, a silencing mechanism driven by METTL3-mediated m6A modification. SOCS3 overexpression inhibited MM cell proliferation and migration while inducing apoptosis. Co-culture with SOCS3-overexpressing MM cells promoted M1-like macrophage polarization, accompanied by suppression of the JAK2/STAT3 signaling pathway. Conversely, SOCS3 silencing promoted malignant behaviors in MM cells and inhibited the M1-like macrophage phenotype. Furthermore, METTL3 silencing exerted tumor-suppressive and immunomodulatory effects similar to those of SOCS3 overexpression, which were reversed by SOCS3 knockdown. In vivo, SOCS3 overexpression potentiated the antitumor efficacy of anti-PD-1 therapy by driving M1-like macrophage polarization and CD8+ T-cell activation.
Conclusion:
SOCS3 exerts dual antitumor efficacy in MM by suppressing malignant tumor progression and reprogramming the TME toward M1-like macrophage polarization and CD8+ T-cell activation. Combining SOCS3 restoration with anti-PD-1 therapy provides a preclinical proof-of-concept for potential combinatorial strategies to enhance immune responses in MM.
