Tumor-associated macrophages (TAMs) have a dual role in the tumor microenvironment, mediating both immune activation and suppression. M1-TAMs kill tumor cells, while M2-TAMs are immunosuppressive and promote tumor growth. The activation of TAMs and enhancement of their anti-tumor immune function is a major goal in cancer immunotherapy. Here, we report a novel pyrazole derivative, IHMT-140, which reprograms tumor-promoting M2 macrophages into tumor-suppressing M1 macrophages, thereby inhibiting tumor growth. Mechanistically, IHMT-140 raises lysosomal pH in M2 macrophages, blocking autophagy and activating MAPK and NF-κB signaling, which induces M2-TAMs to M1-TAMs and mediates the anti-tumor response. As a potential immunomodulator, IHMT-140 provides not only a new tool for studying TAM reprogramming, but also a foundation for developing related immunotherapies. All animal experimental protocols were approved by the Hefei Institutes of Physical Science, Chinese Academy of Sciences, with approval number DWLL-2023-116.
| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |