We demonstrated that M2‐like TAMs activate the PI3K/Akt/HIF‐1α/CA9 pathway in the malignant glioma cells via SPP1‐CD44‐mediated intercellular interaction to promote the recurrence of malignant glioma, which revealed the mechanism of increased drug resistance in recurrent malignant glioma to provide new targets for the drug development. Here, CD44 is linked to malignant glioma.