Metabolic remodeling in tumor-associated macrophages contributing to antitumor activity of cryptotanshinone by...

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Tumor-associated macrophages (TAMs) often exhibit M2/repair phenotypes, promoting tumor growth.
• Repolarizing TAMs to M1/kill phenotypes is a promising cancer immunotherapy strategy.
• Cryptotanshinone (CPT) is a natural compound with potential immunomodulatory effects.

Purpose of the Study:

• To investigate the potential of CPT as an antitumor immune modulator.
• To elucidate the mechanism by which CPT influences TAM polarization.
• To evaluate the efficacy of CPT in preclinical models of triple-negative breast cancer (TNBC).

Main Methods:

• Utilized an orthotopic TNBC implantation mouse model.
• Co-cultured TNBC cells with CPT-treated macrophages.
• Investigated CPT's effects on mitochondrial function, autophagy, and the ASK1/TRAF6 signaling pathway.
• Assessed TAM polarization in response to CPT treatment.

Main Results:

• CPT treatment effectively switched TAMs from M2 to M1 phenotype, leading to tumor regression.
• CPT inhibited TNBC cell proliferation and motility in vitro.
• CPT suppressed tumor formation in vivo and modulated mitochondrial oxidative phosphorylation and fusion.
• CPT's mechanism involves autophagy and the TRAF6-ASK1 pathway, with differential effects on M1 and M2 macrophages.

Conclusions:

• CPT acts as an antitumor immune modulator by repolarizing TAMs to an M1 phenotype.
• CPT's mechanism involves regulating mitochondrial function and the ASK1 pathway.
• CPT demonstrates therapeutic potential as a natural compound for cancer immunotherapy via macrophage-based strategies.