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

Area of Science:

• Oncology
• Immunology
• Medicinal Chemistry

Background:

• Tumor-associated macrophages (TAMs), particularly the M2 phenotype, are crucial drivers of tumor progression.
• Targeting TAMs presents a promising strategy for developing novel anti-tumor therapies.
• Onionin A (ONA), a cyclic sulfur compound, previously demonstrated efficacy in suppressing M2-like TAMs and tumor progression.

Purpose of the Study:

• To discover novel cyclic sulfur compounds with enhanced anti-tumor activity compared to Onionin A.
• To investigate the mechanism by which these compounds modulate macrophage polarization and STAT3 activation.
• To evaluate the in vivo efficacy of candidate compounds in a tumor-bearing mouse model.

Main Methods:

• Screening of 81 cyclic sulfur compounds for their ability to inhibit M2-like polarization in human monocyte-derived macrophages (HMDMs).
• Assessment of STAT3 activation in HMDMs and tumor cells upon stimulation with IL-10 and tumor culture supernatant (TCS).
• Evaluation of anti-tumor effects in co-culture systems and in an LM8 tumor-bearing mouse model.

Main Results:

• Three novel cyclic sulfur compounds significantly inhibited IL-10- and TCS-induced M2-polarization of HMDMs.
• These compounds suppressed STAT3 activation in HMDMs but not in tumor cells, suggesting a specific mechanism of action.
• Candidate compounds inhibited tumor cell proliferation in co-cultures with HMDMs and demonstrated significant tumor growth and metastasis inhibition in vivo.

Conclusions:

• Novel cyclic sulfur compounds effectively target M2-like TAMs and suppress tumor progression.
• These compounds represent promising candidates for developing new anti-tumor therapies by modulating macrophage polarization.
• The findings highlight the therapeutic potential of targeting TAMs through specific small molecules.