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Cyclic sulfur compounds targeting macrophage polarization into M2/protumor phenotype and their anti-tumor effects


Tumor-associated macrophages (TAMs), especially the M2-like phenotype, promote tumor progression, making them candidate targets for anti-tumor therapy. We previously discovered a cyclic sulfur compound, Onionin A (ONA), which suppresses tumor progression by inhibiting the M2-polarization of TAMs. In the present study, we sought to find new candidate compounds possessing a stronger effect compared to ONA by exploring compounds with structures similar to those of ONA among several cyclic sulfur compounds. A total of 81 cyclic sulfur compounds were screened, and their effects on macrophage polarization toward an M2-like phenotype were tested using human monocyte-derived macrophages (HMDMs). The anti-tumor effects of the identified candidate compounds were examined in a tumor-bearing mouse model. Three candidate compounds inhibited both IL-10- and tumor culture supernatant (TCS)-induced M2-polarization of HMDMs. These compounds also suppressed STAT3 activation in HMDMs stimulated by IL-10 and TCS, whereas these compounds had no effect on STAT3 activation in tumor cells. Furthermore, these compounds inhibited tumor cell proliferation under co-culture conditions with HMDMs, indicating that the three candidate compounds suppress tumor proliferation by regulating cell–cell interactions between tumor cells and macrophages. In addition, two of these candidate compounds had inhibitory effects on tumor growth and lung metastasis in the LM8 tumor-bearing mouse model. Our study identified new candidate cyclic sulfur compounds for anti-tumor therapy targeting the M2-polarization of TAMs.

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Enzyme-linked immunosorbent assay


Fetal bovine serum


Human monocyte-derived macrophages


Onionin A


Peripheral blood mononuclear cells




Recombinant human interleukin-10


Real-time quantitative PCR


Tumor-associated macrophages


Tumor culture supernatant


Tumor microenvironment


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We thank Natsuki Abe (Nissan Chemical Industries Ltd.), Takumi Mikashima (Nissan Chemical Industries Ltd), Taito Nishino (Nissan Chemical Industries Ltd), Ms. Takana Motoyoshi (K. I. Stainer, Inc.), and Mr. Takenobu Nakagawa (Kumamoto University) for their technical assistance. This work was supported by JSPS KAKENHI (Grant Numbers 16H05162, 16K09247, 19K09555, and 19K08603).

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Correspondence to Yukio Fujiwara or Yoshihiro Komohara.

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Pan, C., Fujiwara, Y., Horlad, H. et al. Cyclic sulfur compounds targeting macrophage polarization into M2/protumor phenotype and their anti-tumor effects. Cancer Immunol Immunother 71, 1331–1343 (2022).

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  • Tumor-associated macrophages
  • Cyclic sulfur compounds
  • Tumors
  • STAT3
  • M2-polarization