Oxymatrine attenuates melanoma progression and metastasis through SORBS2-mediated suppression of M2 macrophage polarization PMID: 41956023

ADC Targets in Oncology

2026-04-10

Oxymatrine attenuates melanoma progression and metastasis through SORBS2-mediated suppression of M2 macrophage polarization

Phytomedicine. 2026 Jun:155:158148. doi: 10.1016/j.phymed.2026.158148.

Xin Li ¹ , Yanhua Ou ² , Jinling Chen ³ , Junlong Xiong ⁴ , Fangwen Xu ² , Yaqian Hu ² , Yuhan Chen ⁵ , Kunran Bai ³ , Jingyi Chen ³ , Yong Meng ⁶ , Jun He ⁷ , Caiyong Lai ⁸ , Haitao Niu ⁹

Affiliations

1. The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Dongguan, 523573, China; School of Medicine, Jinan University, Guangzhou, 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, School of Medicine, Jinan University, Guangzhou, 510632, China; Guangzhou Key Laboratory for Germ-Free Animals and Microbiome Application, Institute of Laboratory Animal Sciences, Jinan University, Guangzhou, 510632, China.
2. School of Medicine, Jinan University, Guangzhou, 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, School of Medicine, Jinan University, Guangzhou, 510632, China; Guangzhou Key Laboratory for Germ-Free Animals and Microbiome Application, Institute of Laboratory Animal Sciences, Jinan University, Guangzhou, 510632, China.
3. Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, School of Medicine, Jinan University, Guangzhou, 510632, China; Guangzhou Key Laboratory for Germ-Free Animals and Microbiome Application, Institute of Laboratory Animal Sciences, Jinan University, Guangzhou, 510632, China; School of Basic Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China.
4. State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou 510642, China.
5. School of Medicine, Jinan University, Guangzhou, 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, School of Medicine, Jinan University, Guangzhou, 510632, China; Guangzhou Key Laboratory for Germ-Free Animals and Microbiome Application, Institute of Laboratory Animal Sciences, Jinan University, Guangzhou, 510632, China; School of Basic Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China.
6. Department of Veterinary Preclinical Sciences, Faculty of Veterinary Medicine, Universities Putra Malaysia, 43400 UPM Serdang, Malaysia.
7. Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, School of Medicine, Jinan University, Guangzhou, 510632, China; Guangzhou Key Laboratory for Germ-Free Animals and Microbiome Application, Institute of Laboratory Animal Sciences, Jinan University, Guangzhou, 510632, China. Electronic address: [email protected].
8. The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Dongguan, 523573, China. Electronic address: [email protected].
9. The Sixth Affiliated Hospital of Jinan University (Dongguan Eastern Central Hospital), Dongguan, 523573, China; School of Medicine, Jinan University, Guangzhou, 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, School of Medicine, Jinan University, Guangzhou, 510632, China; Guangzhou Key Laboratory for Germ-Free Animals and Microbiome Application, Institute of Laboratory Animal Sciences, Jinan University, Guangzhou, 510632, China. Electronic address: [email protected].

Abstract

Background: Melanoma is an aggressive malignancy characterized by a highly immunosuppressive tumor microenvironment (TME), in which tumor-associated macrophages (TAMs) play a key role. Although oxymatrine (OMT) has been shown to exert Anticancer effects, its mechanism of action in melanoma, particularly its interaction with Sorbin and SH3 Domain-Containing Protein 2 (SORBS2), remains poorly understood.

Purpose: To elucidate the molecular mechanisms by which oxymatrine inhibits melanoma growth and metastasis, suppresses M2-like macrophage polarization, and remodels the TME.

Methods: Cell viability, cell migration, and Apoptosis assays were used to assess the effects of oxymatrine on melanoma cells. RNA Sequencing (RNA-seq) was performed to identify oxymatrine's potential target. The candidate target, SORBS2, was validated through molecular docking and surface plasmon resonance (SPR) to confirm its binding to oxymatrine. Western blotting and qRT-PCR were additionally used to measure SORBS2 expression for further validation. SORBS2-overexpressing or SORBS2-knockout cells and macrophage-melanoma co-culture systems were used to explore oxymatrine's effects on M2-like TAM polarization.

Results: Oxymatrine inhibited melanoma proliferation and migration while inducing Apoptosis. In vivo, oxymatrine suppressed tumor growth and metastasis. Mechanistically, oxymatrine upregulated SORBS2 expression, suppressed M2-like macrophage polarization, reduced the secretion of TGF-β and IL-10, and enhanced antitumor immunity. SORBS2 overexpression mimicked oxymatrine's effects: it inhibited M2-like macrophage polarization and reduced TGF-β and IL-10 secretion, and thereby reshaped the immunosuppressive TME to enhance antitumor immunity.

Conclusion: These findings suggest that oxymatrine exerts anti-melanoma effects potentially by upregulating SORBS2, which in turn inhibits M2-like polarization and remodels the TME. This SORBS2-mediated mechanism provides a novel strategy for melanoma immunotherapy.

Keywords

M2-like macrophage polarization; Melanoma; Metastasis; Oxymatrine; SORBS2.