Upregulation of ZFP36L1 promoted macrophage polarisation towards the SPP1<sup>+</sup> phenotype, which then bound to CD44 on tumour cells to accelerate NSCLC progression.<h4>Conclusion</h4>Under hypoxia, ZFP36L1 transcriptionally regulates SPP1 to reduce the macrophage CXCL9:SPP1 ratio, thereby driving NSCLC malignancy. Here, CD44 is linked to non-small cell lung carcinoma.