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Cryptotanshinone suppresses ESCC metastasis by inhibiting macrophage polarization: A mechanistic study elucidating
Yifei Yin1, Manxuan Zhu2, Yixin Zhang2
1Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310053, China.
Background:
Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with a poor prognosis, characterized by early metastasis and high mortality rates. Cryptotanshinone (CTS), a diterpenoid quinone, has been extensively studied for its diverse pharmacological effects, particularly its anti-tumor properties, however, its therapeutic potential and mechanisms in the treatment of ESCC remain unclear.
Objective:
This study aimed to examine the impact of CTS on the polarization of TAMs and its subsequent role in inhibiting the metastasis of ESCC, both as a monotherapy and in combination with cisplatin.
Methods:
THP-1 cells were differentiated into M0, M2, and TAM-like macrophages using PMA, IL-4, and ESCC cell-conditioned medium. CTS's effects on macrophage polarization were analyzed via flow cytometry, RT-qPCR, Western blot, and ELISA. The impact of macrophage-conditioned media on ESCC cell migration and invasion was assessed through wound healing and transwell assays. Molecular mechanisms were confirmed using molecular docking, the cellular thermal shift assay (CETSA), and drug affinity responsive target stabilization assay (DARTS). An in vivo footpad xenograft model in nude mice, co-inoculated with KYSE150 cells and TAMs, tested the anti-metastatic effects of CTS with cisplatin.
Results:
Within the tumor microenvironment of ESCC, TAMs are polarized into a pro-metastatic M2 phenotype. Our findings indicate that CTS disrupts this process by directly targeting the WNT2 protein, thereby interfering with the WNT2/STAT3/SOX4 signaling feedback loop. This disruption leads to a reduction in M2 polarization and a decrease in the secretion of pro-tumorigenic factors from TAMs. As a result, CTS attenuates the pro-tumorigenic effects of TAMs on ESCC cells and, when used in conjunction with cisplatin, synergistically inhibits ESCC metastasis.
Conclusion:
This study demonstrates that CTS reverses the M2 polarization of TAMs by inhibiting the WNT2/STAT3/SOX4 feedback loop, thereby suppressing ESCC metastasis. These findings underscore the potential of CTS as a therapeutic agent that mitigates the pro-tumoral tumor microenvironment and enhances the efficacy of conventional chemotherapy such as cisplatin.
